EP4222139A1 - Administration topique de propionate de 2-(diéthylamino)éthyl-2-(4-isobutylphényle) pour le traitement de maladies - Google Patents

Administration topique de propionate de 2-(diéthylamino)éthyl-2-(4-isobutylphényle) pour le traitement de maladies

Info

Publication number
EP4222139A1
EP4222139A1 EP21818935.5A EP21818935A EP4222139A1 EP 4222139 A1 EP4222139 A1 EP 4222139A1 EP 21818935 A EP21818935 A EP 21818935A EP 4222139 A1 EP4222139 A1 EP 4222139A1
Authority
EP
European Patent Office
Prior art keywords
isobutylphenyl
propionate
diethylamino
ethyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21818935.5A
Other languages
German (de)
English (en)
Inventor
Lina Xu
Chongxi Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Techfields Inc
Original Assignee
Techfields Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Techfields Inc filed Critical Techfields Inc
Publication of EP4222139A1 publication Critical patent/EP4222139A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings

Definitions

  • the present disclosure relates to the field of medical application, in particular use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate, and pharmaceutically acceptable salts thereof, for the treatment of pains and/or inflammation.
  • Ibuprofen i.e., 2- (4-isobutylphenyl) propionic acid, a non-steroidal anti-inflammatory drug (NSAID)
  • NSAID non-steroidal anti-inflammatory drug
  • Ibuprofen is a known medicine with analgesic, antiphlogistic and antipyretic properties, that is used widely for treatment of symptoms in relation with various diseases, for example, inflammatory diseases and pains, such as rheumatic diseases, headaches, migraines, toothaches, back aches, muscle pain, post-operative pain, and the like.
  • Ibuprofen is usually administered through oral administration to reach the action site of a condition or disease. As disclosed in U.S. Patent 9,872,846, with an administration dose up to about 50 mg/kg or even 200 mg/kg, ibuprofen was administered orally for treating the patients.
  • the present disclosure relates to use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof for treatment of symptoms that can be treated with Ibuprofen.
  • the present disclosure relates to a method of treatment including administrating 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof for use in treatment of osteoarthritis.
  • the present disclosure relates to use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof in the manufacture of a medicament.
  • the present disclosure relates to a kit including 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a therapeutic system including a composition including 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a dosage form in which a certain concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a device capable of administering a certain unit dose.
  • the present disclosure relates to topical administration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a certain optimum dosage forms and/or dosages of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a method of treatment of a subject, including topical administrating 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof to the subject, in particular to one or more sites of the subject, in an amount of about 1 mg to about 80 mg, in particular 1 mg to 80 mg, per day, in particular per day per site.
  • the present disclosure relates to 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof for use in treatment of a subject, wherein 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 1 mg to about 80 mg, in particular 1 mg to 80 mg, per day, in particular per day per site.
  • the present disclosure relates to use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof in the manufacture of a medicament, wherein 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered, to a subject, in particular to one or more sites of a subject, in an amount of about 1 mg to about 80 mg, in particular 1 mg to 80 mg, per day, in particular per day per site.
  • the present disclosure relates to a kit for treatment of a subject, including 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof for being topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 1 mg to about 80 mg, in particular 1 mg to 80 mg, per day, in particular per day per site.
  • the present disclosure relates to a therapeutic system for treatment of a subject, including a composition of which 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is an active ingredient, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate present as a free base or as a pharmaceutically acceptable salt, wherein in the system, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 1 mg to about 80 mg, in particular 1 mg to 80 mg, per day, in particular per day per site.
  • the present disclosure relates to a method of treatment of a subject, including topical administrating 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof to the subject, in particular to one or more sites of the subject, in an amount of about 0.1 mg to about 40 mg, in particular 0.1 mg to 40 mg, per dose, in particular per dose per site.
  • the present disclosure relates to 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof for use in treatment of a subject, wherein 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 0.1 mg to about 40 mg, in particular 0.1 mg to 40 mg, per dose, in particular per dose per site.
  • the present disclosure relates to use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof in the manufacture of a medicament, wherein 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered, to a subject, in particular to one or more sites of a subject, in an amount of about 0.1 mg to about 40 mg, in particular 0.1 mg to 40 mg, per dose, in particular per dose per site.
  • the present disclosure relates to a kit for treatment of a subject, including 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof for being topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 0.1 mg to about 40 mg, in particular 0.1 mg to 40 mg, per dose, in particular per dose per site.
  • the present disclosure relates to a therapeutic system for treatment of a subject, including a composition of which 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is an active ingredient, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate present as a free base or as a pharmaceutically acceptable salt, wherein in the system, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 0.1 mg to about 40 mg, in particular 0.1 mg to 40 mg, per dose, in particular per dose per site.
  • the present disclosure relates to a method of treatment of a subject, including topical administrating 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof to the subject, in particular to one or more sites of the subject, in an amount of about 5 ⁇ g/cm 2 to about 2 mg/cm 2 , in particular 5 ⁇ g/cm 2 to 2 mg/cm 2 , per dose, in particular per dose per site.
  • the present disclosure relates to 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof for use in treatment of a subject, wherein 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 5 ⁇ g/cm 2 to about 2 mg/cm 2 , in particular 5 ⁇ g/cm 2 to 2 mg/cm 2 , per dose, in particular per dose per site.
  • the present disclosure relates to use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof in the manufacture of a medicament, wherein 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered, to a subject, in particular to one or more sites of a subject, in an amount of about 5 ⁇ g/cm 2 to about 2 mg/cm 2 , in particular 5 ⁇ g/cm 2 to 2 mg/cm 2 , per dose, in particular per dose per site.
  • the present disclosure relates to a kit for treatment of a subject, including 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof for being topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 5 ⁇ g/cm 2 to about 2 mg/cm 2 , in particular 5 ⁇ g/cm 2 to 2 mg/cm 2 , per dose, in particular per dose per site.
  • the present disclosure relates to a therapeutic system for treatment of a subject, including a composition of which 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is an active ingredient, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate present as a free base or as a pharmaceutically acceptable salt, wherein in the system, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered to the subject, in particular to one or more sites of the subject, in an amount of about 5 ⁇ g/cm 2 to about 2 mg/cm 2 , in particular 5 ⁇ g/cm 2 to 2 mg/cm 2 , per dose, in particular per dose per site.
  • the present disclosure relates to a dosage form, wherein a concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in the dosage form is about 10 mg/mL to about 200 mg/mL, in particular 10 mg/mL to 200 mg/mL, or about 10 mg/g to about 200 mg/g, in particular 10 mg/g to 200 g.
  • the present disclosure relates to a device capable of administering a unit dose of about 0.5 mg to about 30 mg, in particular 0.5 mg to 30 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a spray capable of spraying a unit dose of about 0.5 mg to about 30 mg, in particular 0.5 mg to 30 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof.
  • the present disclosure is intended to assess the efficacy and safety of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate when administered to the knee as a topical spray in subjects with OA of the knee.
  • Figure 1 is a study schema of the Phase 1 clinical study in some embodiments of the present disclosure.
  • Figure 2 is a line chart of mean (SD) 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate plasma concentration versus time by treatment on Day 1 (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 3 is a line chart of mean (SD) 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate plasma concentration versus time by treatment on Day 12 (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 4 is a line chart of mean (SD) 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate plasma concentration versus time by treatment on Day 1 (semi-log scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 5 is a line chart of mean (SD) 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate plasma concentration versus time by treatment on Day 12 (semi-log scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 6 is a line chart of mean (SD) 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate plasma concentration versus time by treatment on Day 1 from time 0 to 24 hours (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 7 is a line chart of mean (SD) 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate plasma concentration versus time by treatment on Day 12 from time 0 to 48 hours (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 8 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 1 (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 9 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 12 (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 10 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 1 (semi-log scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 11 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 12 (semi-log scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 12 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 1 from time 0 to 48 hours (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • SD mean
  • Figure 12 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 1 from time 0 to 48 hours (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 13 is a line chart of mean (SD) ibuprofen plasma concentration versus time by treatment on Day 12 from time 0 to 48 hours (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • SD mean
  • ibuprofen plasma concentration versus time by treatment on Day 12 from time 0 to 48 hours (linear scale) for all randomized subjects in Phase 1 Clinical Study in some embodiments of the present disclosure.
  • Figure 14 is a line chart of changes in WOMAC Pain Subscale Scores (mm) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 15 is a line chart of changes in WOMAC Pain Subscale Scores (%) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 16 is a line chart of changes in WOMAC Pain Scores (mm) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) (adjusted by 58.3%of the testing drug amount) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 17 is a line chart of changes in WOMAC Pain Scores (%) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) (adjusted by 58.3%of the testing drug amount) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 18 is a line chart of changes in WOMAC Joint Stiffness Subscale Scores (mm) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 19 is a line chart of changes in WOMAC Joint Stiffness Subscale Scores (%) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 20 is a line chart of changes in WOMAC Joint Stiffness Subscale Scores (mm) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) (adjusted by 58.3%of the testing drug amount) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 21 is a line chart of changes in WOMAC Joint Stiffness Subscale Scores (%) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) (adjusted by 58.3%of the testing drug amount) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 22 is a line chart of changes in WOMAC Difficulty Performing Daily Activities Subscale Scores (mm) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 23 is a line chart of changes in WOMAC Difficulty Performing Daily Activities Subscale Scores (%) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 24 is a line chart of changes in WOMAC Difficulty Performing Daily Activities Subscale Scores (mm) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) (adjusted by 58.3%of the testing drug amount) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • Figure 25 is a line chart of changes in WOMAC Difficulty Performing Daily Activities Subscale Scores (%) for transdermal 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate 8.75, 17.5 and 35 mg/knee b.i.d. at week 2, 4, 8 and 12, and follow up (7 days after the treatment was stopped) (adjusted by 58.3%of the testing drug amount) in the Phase 2 clinical study in some embodiments of the present disclosure.
  • the present disclosure relates to a pharmaceutical composition capable of penetrating cartilage and methods of using the pharmaceutical composition for treating pains, especially osteoarthritis of humans and animals.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises” ) , “having” (and any form of having, such as “have” and “has” ) , “including” (and any form of including, such as “includes” and “include” ) or “containing” (and any form of containing, such as “contains” and “contain” ) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • compositions, a combination, a constitution, a juxtaposition, or a group are described as including (or comprising) components A, B, C, and/or D
  • the composition can contain A alone; B alone; C alone; D alone; A and B in combination; A and C in combination; A and D in combination; B and C in combination; B and D in combination; C and D in combination; A, B, and C in combination; A, B, and D in combination; A, C, and D in combination; B, C, and D in combination; or A, B, C, and D in combination.
  • the term “about” or “approximately” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.
  • the terms “about” or “approximately” usually mean within 10%, in particular within 9%, in particular within 8%, in particular within 7%, in particular within 6%, in particular within 5%, in particular within 4%, in particular within 3%, in particular within 2%, in particular within 1%, of a given value or range.
  • treat comprises treatment or therapeutic regimen relieving, reducing or alleviating at least one symptom in a patient or effecting a delay of progression of a proliferative disorder.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as osteoarthritis.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disorder) and/or reduce the risk of developing or worsening a disorder.
  • the term “dose” means a drug or active component taken each time by an individual subject, in particular the total amount of a drug or active component taken each time by an individual subject, for one site.
  • dosage form means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
  • unit dose refers to a dosage form that is configured to deliver a specified quantity or dosage of composition or component thereof.
  • dosage forms for topical administration include, but are not limited to, transdermal patch, cream, foam, gel, lotion, ointment, paste, powder, shake lotion, solid, sponge, tape, tinkture, vapor, injection, drops, rinces, spray, and solution.
  • a “unit dose” or “dosage unit” may be configured to provide a full unit dose or fraction thereof (e.g., 1/2, 1/3, or 1/4 of a dose) .
  • a predetermined quantity in each unit dose can depend on factors that include, but are not limited to, the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of creating and administering such unit doses.
  • a unit dose may be, a transdermal patch, a spray, i.e., once spray in the spray application, a droplet of the dropping application, a certain length of the tape, rice-sized or bean-sized ointment, or a scoop or a spoon of ointment.
  • Unit dose measuring devices such as a cup, scoop, syringe, dropper, spoon, or colonic irrigation device, may hold the dosage form, for instance cream, foam, gel, lotion, ointment, paste, powder, shake lotion and solid, a measured quantity of composition equaling a full unit dose or fraction thereof (e.g., 1/2, 1/3, or 1/4 of a dose) .
  • a full unit dose or fraction thereof e.g. 1/2, 1/3, or 1/4 of a dose
  • the kit may include instructions regarding the size of the unit dose, or fraction thereof.
  • pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a patient without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • composition is defined herein to refer to a substance or a mixture or solution containing at least one therapeutic agent to be administered to a patient, in order to prevent or treat, in particular to treat a particular disease or condition affecting the patient.
  • the therapeutic agent may be administered each day in a single unit dose or multiple unit doses and/or administered each day in a single dose (once per day, q.d. ) or divided doses (more than once per day, e.g., twice per day, b.i.d. ) .
  • day refers to either one calendar day in any time zone or one 24-hour period.
  • patient or “subject” is intended to include animals, including warm-blooded animals.
  • patients include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the patient is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a disease, for instance suffering from osteoarthritis.
  • transdermal administration means administration of a transdermal dose, unit dose or dosage form
  • transdermally administering means administering a transdermal dose, unit dose or dosage form
  • transdermally administered means administered by a transdermal dose, unit dose or dosage form. That a patient and/or subject is “transdermally administered” is equivalent to that a patient and/or subject is subjected to a “transdermal administration” . “Transdermally administering” to a patient and/or subject is equivalent to subjecting a “transdermal administration” to a patient and/or subject.
  • the term “site” is the region/location of a human body where a symptom was found, for example, joint, muscle, bone and/or cartilage, etc., itself having the symptom, particular the pain, the inflammation and/or the disease, particularly the symptom, pain, inflammation and/or disease of joint, muscle, bone and/or cartilage, etc., more particularly osteoarthritis; and/or the joint, muscle, bone and/or cartilage, etc., where a cause of the symptom, particular the pain, the inflammation and/or the disease of joint, muscle, bone and/or cartilage etc., more particularly osteoarthritis, is located.
  • the term “administrating to the site” (of the subject) means administrating to: (a) the place on the skin and/or body surface which is in correspondence with, or, close to the “site” ; and/or (b) the place on the skin and/or body surface that provides an accessible route to the “site” .
  • the site could be the joint itself suffering from, at risk of suffering from, or potentially capable of suffering from the symptom, particular the pain, the inflammation and/or disease of joint, muscle, bone and/or cartilage, etc., more particularly osteoarthritis, while administrating to the site could be administrating to the skin and/or body surface near, in particular within about 1 cm to about 15 cm, in particular about 3 cm to about 10 cm, in particular a distance selected from about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm, about 15 cm, from the joint, muscle, bone or cartilage etc., and/or an environment about 1 cm to about 15 cm, in particular about 3 cm to about 10 cm, in particular a distance selected from about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm,
  • the term “close” or “close to” means within about 1 cm to about 15 cm, in particular about 3 cm to about 10 cm, in particular a distance selected from about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm, about 15 cm, from the center of the site, i.e.
  • joint, muscle, bone or cartilage etc. and/or an environment about 1 cm to about 15 cm, in particular about 3 cm to about 10 cm, in particular a distance selected from about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm, about 15 cm, around all directions of the center of the site, i.e. joint, muscle, bone or cartilage, etc.
  • the term “symptom” refers to any symptoms such as diseases, inflammation, pain, fever, gout, dysmenorrhea, joint swelling, morning stiffness, rheumatoid disorders, or injury.
  • the symptom could be pain or inflammation related to musculoskeletal system, for instance arthritis, in particular osteoarthritis or rheumatoid arthritis.
  • the term “pain” refers to any pain such as acute pain, bone pain, joint pain, muscle pain, cartilage pain, migraine pain, headache, cluster headache, menstrual cramps, neuropathic pain, post-operative pain, chronic lower back pain, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, injury pain, pain during labor and delivery, pain resulting from burns, sunburn, gout, lupus, fibromyalgia, post-partum pain, angina pain, cystitis, inflammation, arthritis pain, septic arthritis pain, osteoarthritis pain, juvenile rheumatoid arthritis pain, ankylosing spondylitis and dysmenorrhea.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1 mg to about 64 mg, in particular 1 mg to 64 mg, per day, in particular per day per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 2 mg to about 56 mg, in particular 2 mg to 56 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 3 mg to about 48 mg, in particular 3 mg to 48 mg, per day, in particular per day per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 40 mg, in particular 4 mg to 40 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 32 mg, in particular 4 mg to 32 mg, per day, in particular per day per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 8 mg to about 32 mg, in particular 8 mg to 32 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 8 mg to about 18 mg, in particular 8 mg to 18 mg, per day, in particular per day per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 8 mg, in particular 4 mg to 8 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 8 mg to about 16 mg, in particular 8 mg to 16 mg, per day, in particular per day per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 16 mg to about 32 mg, in particular 16 mg to 32 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 4.5 mg, 9 mg, 13.5 mg, 18 mg, 22.5 mg, 27 mg, 31.5 mg, 36 mg, 40.5 mg, 45 mg, 49.5 mg, 54 mg, 58.5 mg, 63 mg, 67.5 mg and 72 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg,
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 4.375 mg, 8.75 mg, 13.125 mg, 17.5 mg, 21.875 mg, 26.25 mg, 30.625 mg, 35 mg, 39.375 mg, 43.75 mg, 48.125 mg, 52.5 mg, 56.875 mg, 61.25 mg, 65.625 mg, and 70 mg, per day, in particular per day per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.1 mg to about 40 mg, in particular 0.1 mg to 40 mg per dose, in particular per dose per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1 mg to about 32 mg, in particular 1 mg to 32 mg, per dose, in particular per dose per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.5 mg to about 24 mg, in particular 1.5 mg to 24 mg, per dose, in particular per dose per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 2 mg to about 20 mg, in particular 2 mg to 20 mg, per dose, in particular per dose per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 18 mg, in particular 4 mg to 18 mg, per dose, in particular per dose per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 8 mg, in particular 4 mg to 8 mg, per dose, in particular per dose per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 8 mg to about 16 mg, in particular 8 mg to 16 mg, per dose, in particular per dose per site. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 16 mg to about 32 mg, in particular 16 mg to 32 mg, per dose, in particular per dose per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 1 mg, 2.25 mg, 4.5 mg, 6.75 mg, 9 mg, 11.25 mg, 13.5 mg, 15.75 mg, 18 mg, 20.25 mg, 22.5 mg, 24.75 mg, 27 mg, 29.25 mg, 31.5 mg, 33.75 mg, and 36 mg, per dose, in particular per dose per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.05 mg, 2.1 mg, 2.15 mg, 2.2 mg, 2.25 mg, 2.3 mg, 2.35 mg, 2.4 mg, 2.45 mg, 2.5 mg, 2.55 mg, 2.6 mg, 2.65 mg, 2.7 mg, 2.75 mg, 2.8 mg, 2.85 mg, 2.9 mg, 2.95 mg, 3 mg, 3.05 mg, 3.1 mg, 3.15 mg, 3.2 mg, 3.25 mg, 3.3 mg, 3.35
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 2.1875 mg, 4.375 mg, 6.5625 mg, 8.75 mg, 10.9375 mg, 13.125 mg, 15.3125 mg, 17.5 mg, 19.6875 mg, 21.875 mg, 24.0625 mg, 26.25 mg, 28.4375 mg, 30.625 mg, 32.8125 mg, and 35 mg, per dose, in particular per dose per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 5 ⁇ g/cm 2 to about 4 mg/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 5 ⁇ g/cm 2 to about 2 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 10 ⁇ g/cm 2 to about 2 mg/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 30 ⁇ g/cm 2 to about 2 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 35 ⁇ g/cm 2 to about 1.5 mg/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 40 ⁇ g/cm 2 to about 1 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 45 ⁇ g/cm 2 to about 750 ⁇ g/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 48 ⁇ g/cm 2 to about 600 ⁇ g/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 50 ⁇ g/cm 2 to about 500 ⁇ g/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 60 ⁇ g/cm 2 to about 2 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 80 ⁇ g/cm 2 to about 2 mg/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 90 ⁇ g/cm 2 to about 1.5 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 96 ⁇ g/cm 2 to about 1.2 mg/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 100 ⁇ g/cm 2 to about 1 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 45 ⁇ g/cm 2 to about 90 ⁇ g/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 60 ⁇ g/cm 2 to about 120 ⁇ g/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 90 ⁇ g/cm 2 to about 180 ⁇ g/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 120 ⁇ g/cm 2 to about 240 ⁇ g/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 180 ⁇ g/cm 2 to about 360 ⁇ g/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 240 ⁇ g/cm 2 to about 480 ⁇ g/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 360 ⁇ g/cm 2 to about 720 ⁇ g/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 480 ⁇ g/cm 2 to about 960 ⁇ g/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 720 ⁇ g/cm 2 to about 1.44 mg/cm 2 per dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 960 ⁇ g/cm 2 to about 1.92 mg/cm 2 per dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 5 ⁇ g/cm 2 , 5.5 ⁇ g/cm 2 , 6 ⁇ g/cm 2 , 6.5 ⁇ g/cm 2 , 7 ⁇ g/cm 2 , 7.5 ⁇ g/cm 2 , 8 ⁇ g/cm 2 , 8.5 ⁇ g/cm 2 , 9 ⁇ g/cm 2 , 9.5 ⁇ g/cm 2 , 10 ⁇ g/cm 2 , 11 ⁇ g/cm 2 , 12 ⁇ g/cm 2 , 13 ⁇ g/cm 2 , 14 ⁇ g/cm 2 , 15 ⁇ g/cm 2 , 16 ⁇ g/cm 2 , 17 ⁇ g/cm 2 , 18 ⁇ g/cm 2 , 19 ⁇ g/c
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount selected from a group consisting of 37.5 ⁇ g/cm 2 , 75 ⁇ g/cm 2 , 112.5 ⁇ g/cm 2 , 150 ⁇ g/cm 2 , 187.5 ⁇ g/cm 2 , 225 ⁇ g/cm 2 , 262.5 ⁇ g/cm 2 , 300 ⁇ g/cm 2 , 337.5 ⁇ g/cm 2 , and 375 ⁇ g/cm 2 per dose.
  • the subject is a warm-blooded animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate. In some embodiments, the subject is a human. In some embodiments, the subject is a human adult. In some embodiments, the age of the adult is more than or equal to an age selected from a group consisting of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from symptoms.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from symptoms, in particular a subject suffering from, at risk of suffering from, or potentially capable of suffering from diseases, inflammation, pain, fever, gout, dysmenorrhea, joint swelling, morning stiffness, rheumatoid disorders, or injury.
  • the symptoms are diseases, inflammation, pain, fever, gout, dysmenorrhea, joint swelling, morning stiffness, rheumatoid disorders, or injury.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from symptoms, in particular a subject suffering from, at risk of suffering from, or potentially capable of suffering from diseases, inflammation or pain.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from pain.
  • the subject is, and/or the medicament is for, subject suffering from, at risk of suffering from, or potentially capable of suffering from joint pain, bone pain, cartilage pain, muscle pain, dental pain, headache, dysmenorrhea or menstrual cramps.
  • the pain is joint pain.
  • the pain is bone pain.
  • the pain is cartilage pain.
  • the pain is muscle pain.
  • the pain is dental pain.
  • the pain is headache.
  • the pain is dysmenorrhea.
  • the pain is menstrual cramps.
  • the pain is arthritis pain.
  • the pain is osteoarthritis pain.
  • the pain is hurt. In some embodiments, the pain is postoperative pain. In some embodiments, the pain is gout pain. In some embodiments, the pain is lupus pain. In some embodiments, the pain is fibromyalgia. In some embodiments, the pain is dysmenorrhea. In some embodiments, the pain is joint swelling. In some embodiments, the pain is morning stiffness. In some embodiments, the pain is rheumatoid disorders. In some embodiments, the pain is minor injury.
  • the pain is a joint pain of one or both knees, one or both ankles, one or both elbows, one or both wrists, one or more neck spines, one or more back spines, one or both shoulders, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • the pain is knee joint pain.
  • the pain is ankle joint pain.
  • the pain is elbow joint pain.
  • the pain is wrist joint pain.
  • the pain is neck spine joint pain.
  • the pain is back spine joint pain.
  • the pain is shoulder joint pain.
  • the pain is hip joint pain.
  • the pain is finger joint pain.
  • the pain is toe joint pain.
  • the pain is a cartilage pain of one or both knees, one or both ankles, one or both elbows, one or both wrists, one or more neck spines, one or more back spines, one or both shoulders, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • the pain is knee cartilage pain.
  • the pain is ankle cartilage pain.
  • the pain is elbow cartilage pain.
  • the pain is wrist cartilage pain.
  • the pain is neck spine cartilage pain.
  • the pain is back spine cartilage pain.
  • the pain is shoulder cartilage pain.
  • the pain is hip cartilage pain.
  • the pain is finger cartilage pain.
  • the pain is toe cartilage pain.
  • the pain is bone pain of head, neck spine, shoulder, upper arm, forearm, palm, finger, shoulder blade, rib, back spine, hip, thigh, calf, sole, or toe bones.
  • the pain is head bone pain. In some embodiments, the pain is neck spine pain. In some embodiments, the pain is shoulder bone pain. In some embodiments, the pain is upper arm bone pain. In some embodiments, the pain is forearm bone pain. In some embodiments, the pain is palm bone pain. In some embodiments, the pain is finger bone pain. In some embodiments, the pain is shoulder blade pain. In some embodiments, the pain is rib pain. In some embodiments, the pain is back spine pain. In some embodiments, the pain is hip bone pain. In some embodiments, the pain is thigh bone pain. In some embodiments, the pain is calf bone pain. In some embodiments, the pain is sole bone pain. In some embodiments, the pain is toe bone pain.
  • the pain is muscle pain of head, neck, shoulder, upper arm, forearm, palm, finger, chest, abdomen, back, hip, thigh, calf, sole, or toe muscles.
  • the pain is head muscle pain. In some embodiments, the pain is neck muscle pain. In some embodiments, the pain is shoulder muscle pain. In some embodiments, the pain is upper arm muscle pain. In some embodiments, the pain is forearm muscle pain. In some embodiments, the pain is palm muscle pain. In some embodiments, the pain is finger muscle pain. In some embodiments, the pain is chest muscle pain. In some embodiments, the pain is abdomen muscle pain. In some embodiments, the pain is back muscle pain. In some embodiments, the pain is hip muscle pain. In some embodiments, the pain is thigh muscle pain. In some embodiments, the pain is calf muscle pain. In some embodiments, the pain is sole muscle pain. In some embodiments, the pain is toe muscle pain.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from inflammation.
  • the subject is, and/or the medicament is for, subject suffering from, at risk of suffering from, or potentially capable of suffering from joint inflammation, bone inflammation, cartilage inflammation, muscle inflammation, or dental inflammation.
  • the inflammation is joint inflammation.
  • the inflammation is bone inflammation.
  • the inflammation is cartilage inflammation.
  • the inflammation is muscle inflammation.
  • the inflammation is dental inflammation.
  • the inflammation is a joint inflammation of one or both knees, one or both ankles, one or both elbows, one or both wrists, one or more neck spines, one or more back spines, one or both shoulders, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • the inflammation is knee joint inflammation.
  • the inflammation is ankle joint inflammation.
  • the inflammation is elbow joint inflammation.
  • the inflammation is wrist joint inflammation.
  • the inflammation is neck spine joint inflammation.
  • the inflammation is back spine joint inflammation.
  • the inflammation is shoulder joint inflammation.
  • the inflammation is hip joint inflammation.
  • the inflammation is finger joint inflammation.
  • the inflammation is toe joint inflammation.
  • the inflammation is a cartilage inflammation of one or both knees, one or both ankles, one or both elbows, one or both wrists, one or more neck spines, one or more back spines, one or both shoulders, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • the inflammation is knee cartilage inflammation.
  • the inflammation is ankle cartilage inflammation.
  • the inflammation is elbow cartilage inflammation.
  • the inflammation is wrist cartilage inflammation.
  • the inflammation is neck spine cartilage inflammation.
  • the inflammation is back spine cartilage inflammation.
  • the inflammation is shoulder cartilage inflammation.
  • the inflammation is hip cartilage inflammation.
  • the inflammation is finger cartilage inflammation.
  • the inflammation is toe cartilage inflammation.
  • the inflammation is bone inflammation of head, neck spine, shoulder, upper arm, forearm, palm, finger, shoulder blade, rib, back spine, hip, thigh, calf, sole, or toe bones.
  • the inflammation is head bone inflammation. In some embodiments, the inflammation is neck spine inflammation. In some embodiments, the inflammation is shoulder bone inflammation. In some embodiments, the inflammation is upper arm bone inflammation. In some embodiments, the inflammation is forearm bone inflammation. In some embodiments, the inflammation is palm bone inflammation. In some embodiments, the inflammation is finger bone inflammation. In some embodiments, the inflammation is shoulder blade inflammation. In some embodiments, the inflammation is rib inflammation. In some embodiments, the inflammation is back spine inflammation. In some embodiments, the inflammation is hip bone inflammation. In some embodiments, the inflammation is thigh bone inflammation. In some embodiments, the inflammation is calf bone inflammation. In some embodiments, the inflammation is sole bone inflammation. In some embodiments, the inflammation is toe bone inflammation.
  • the inflammation is muscle inflammation of head, neck, shoulder, upper arm, forearm, palm, finger, chest, abdomen, back, hip, thigh, calf, sole, or toe muscles.
  • the inflammation is head muscle inflammation. In some embodiments, the inflammation is neck muscle inflammation. In some embodiments, the inflammation is shoulder muscle inflammation. In some embodiments, the inflammation is upper arm muscle inflammation. In some embodiments, the inflammation is forearm muscle inflammation. In some embodiments, the inflammation is palm muscle inflammation. In some embodiments, the inflammation is finger muscle inflammation. In some embodiments, the inflammation is chest muscle inflammation. In some embodiments, the inflammation is abdomen muscle inflammation. In some embodiments, the inflammation is back muscle inflammation. In some embodiments, the inflammation is hip muscle inflammation. In some embodiments, the inflammation is thigh muscle inflammation. In some embodiments, the inflammation is calf muscle inflammation. In some embodiments, the inflammation is sole muscle inflammation. In some embodiments, the inflammation is toe muscle inflammation.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from a disease.
  • the disease is an inflammation.
  • the disease is a joint disease.
  • the disease is a muscle disease.
  • the disease is an arthritis.
  • the disease is selected from a group consisting of osteoarthritis, rheumatoid arthritis, gout, lupus, fibromyalgia, and septic arthritis.
  • the disease is osteoarthritis.
  • the disease is rheumatoid arthritis.
  • the disease is a hurting disease.
  • the disease is a muscle disease, a cartilage disease, or a bone disease. In some embodiments, the disease is a myositis.
  • the joint of the joint disease, arthritis or osteoarthritis is a knee, an ankle, an elbow, a wrist, a neck spine, a back spine, a shoulder, a hip, a finger, and/or a toe.
  • the joint of the joint disease, arthritis or osteoarthritis is a knee.
  • the joint of the joint disease or osteoarthritis is an ankle.
  • the joint of the joint disease, arthritis or osteoarthritis is an elbow.
  • the joint of the joint disease, arthritis or osteoarthritis is a wrist.
  • the joint of the joint disease, arthritis or osteoarthritis is one or more of back spine joints.
  • the joint of the joint disease, arthritis or osteoarthritis is one or more of back spine joints. In some embodiments, the joint of the joint disease, arthritis or osteoarthritis is a shoulder. In some embodiments, the joint of the joint disease, arthritis or osteoarthritis is a hip. In some embodiments, the joint of the joint disease, arthritis or osteoarthritis is a finger. In some embodiments, the joint of the joint disease, arthritis or osteoarthritis is a toe.
  • the osteoarthritis is a knee osteoarthritis, an ankle osteoarthritis, an elbow osteoarthritis, a wrist osteoarthritis, a neck osteoarthritis, a back osteoarthritis, a shoulder osteoarthritis, a hip osteoarthritis, a finger osteoarthritis, and/or a toe osteoarthritis.
  • the osteoarthritis is a knee osteoarthritis.
  • the osteoarthritis is an ankle osteoarthritis.
  • the osteoarthritis is an elbow osteoarthritis.
  • the osteoarthritis is a wrist osteoarthritis.
  • the osteoarthritis is a neck spine osteoarthritis.
  • the osteoarthritis is a back spine osteoarthritis. In some embodiments, the osteoarthritis is a shoulder osteoarthritis. In some embodiments, the osteoarthritis is a hip osteoarthritis. In some embodiments, the osteoarthritis is a finger osteoarthritis. In some embodiments, the osteoarthritis is a toe osteoarthritis.
  • the rheumatoid arthritis is a knee rheumatoid arthritis, an ankle rheumatoid arthritis, an elbow rheumatoid arthritis, a wrist rheumatoid arthritis, a neck rheumatoid arthritis, a back rheumatoid arthritis, a shoulder rheumatoid arthritis, a hip rheumatoid arthritis, a finger rheumatoid arthritis, and/or a toe rheumatoid arthritis.
  • the rheumatoid arthritis is a knee rheumatoid arthritis.
  • the rheumatoid arthritis is an ankle rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is an elbow rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is a wrist rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is a neck spine rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is a back spine rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is a shoulder rheumatoid arthritis.
  • the rheumatoid arthritis is a hip rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is a finger rheumatoid arthritis. In some embodiments, the rheumatoid arthritis is a toe rheumatoid arthritis.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from fever.
  • the subject is, and/or the medicament is for, a subject suffering from, at risk of suffering from, or potentially capable of suffering from gout seizures.
  • the gout seizure is a knee gout seizure, an ankle gout seizure, an elbow gout seizure, a wrist gout seizure, a neck gout seizure, a back gout seizure, a shoulder gout seizure, a hip gout seizure, a finger gout seizure, and/or a toe gout seizure.
  • the gout seizure is a knee gout seizure.
  • the gout seizure is an ankle gout seizure.
  • the gout seizure is an elbow gout seizure.
  • the gout seizure is a wrist gout seizure. In some embodiments, the gout seizure is a neck spine gout seizure. In some embodiments, the gout seizure is a back spine gout seizure. In some embodiments, the gout seizure is a shoulder gout seizure. In some embodiments, the gout seizure is a hip gout seizure. In some embodiments, the gout seizure is a finger gout seizure. In some embodiments, the gout seizure is a toe gout seizure.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to a joint suffering from, at risk of suffering from, or potentially capable of suffering from joint disease.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to a joint suffering from, at risk of suffering from, or potentially capable of suffering from arthritis.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to a joint suffering from, at risk of suffering from, or potentially capable of suffering from osteoarthritis.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more joints suffering from, at risk of suffering from, or potentially capable of suffering from osteoarthritis.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or both knees, one or both ankles, one or both elbows, one or both wrists, one or more neck spines, one or more back spines, one or both shoulders, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • the one or more sites of the subject includes a head, one or both knees, one or both ankles, one or more thighs, one or more calves, one or more soles, one or both elbows, one or both wrists, one or both upper arms, one or both forearms, one or both palms, a neck, a back, one or both shoulders, one side or both sides of chest, an abdomen, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • the one or more sites of the subject includes one knee or two knees. In some embodiments, the one or more sites of the subject includes one knees. In some embodiments, the one or more sites of the subject includes two knees. In some embodiments, the one or more sites of the subject includes one ankle or two ankles. In some embodiments, the one or more sites of the subject includes one thigh or two thighs. In some embodiments, the one or more sites of the subject includes one calf or two calves. In some embodiments, the one or more sites of the subject includes one sole or two soles. In some embodiments, the one or more sites of the subject includes one elbow or two elbows. In some embodiments, the one or more sites of the subject includes one wrist or two wrists.
  • the one or more sites of the subject includes one upper arm or two upper arms. In some embodiments, the one or more sites of the subject includes one forearm or two forearms. In some embodiments, the one or more sites of the subject includes one palm or two palms. In some embodiments, the one or more sites of the subject includes a neck. In some embodiments, the one or more sites of the subject includes a back. In some embodiments, the one or more sites of the subject includes one shoulder or two shoulders. In some embodiments, the one or more sites of the subject includes one side or two sides of chest. In some embodiments, the one or more sites of the subject includes an abdomen. In some embodiments, the one or more sites of the subject includes one side or two side of hips. In some embodiments, the one or more sites of the subject includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fingers. In some embodiments, the one or more sites of the subject includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 toes.
  • the one or more sites of the subject includes one or more joints, one or more muscles, one or more bones, one or more cartilages, and/or one or more soft tissues. In some embodiments, the one or more sites of the subject includes one or more joints. In some embodiments, the one or more sites of the subject includes one or more muscles. In some embodiments, the one or more sites of the subject includes one or more bones. In some embodiments, the one or more sites of the subject includes or one or more cartilages. In some embodiments, the one or more sites of the subject includes or one or more parts of soft tissues.
  • the one or more sites of the subject includes one or more joints, one or more muscles, one or more bones, one or more cartilages, and/or one or more parts of soft tissues suffering from, at risk of suffering from, or potentially capable of suffering from pain.
  • the one or more sites of the subject includes one or more joints suffering from, at risk of suffering from, or potentially capable of suffering from joint pain.
  • the one or more sites of the subject includes one or more muscles suffering from, at risk of suffering from, or potentially capable of suffering from muscle pain.
  • the one or more sites of the subject includes one or more bones suffering from, at risk of suffering from, or potentially capable of suffering from bone pain.
  • the one or more sites of the subject includes or one or more cartilages suffering from, at risk of suffering from, or potentially capable of suffering from cartilage pain. In some embodiments, the one or more sites of the subject includes or one or more parts of soft tissues suffering from, at risk of suffering from, or potentially capable of suffering from soft tissue pain.
  • the one or more sites of the subject includes one or more joints, one or more muscles, one or more bones, one or more cartilages, and/or one or more parts of soft tissues suffering from, at risk of suffering from, or potentially capable of suffering from inflammation.
  • the one or more sites of the subject includes one or more joints suffering from, at risk of suffering from, or potentially capable of suffering from arthritis.
  • the one or more sites of the subject includes one or more joints suffering from, at risk of suffering from, or potentially capable of suffering from osteoarthritis.
  • the one or more sites of the subject includes one or both knee joints, one or both ankle joints, one or both elbow joints, one or both wrist joints, one or more neck spine joints, one or more back spine joints, one or both shoulder joints, one or both of hip joints, one or more of finger joints, and/or one or more of toe joints.
  • the one or more sites of the subject includes one or both knee joints. In some embodiments, the one or more sites of the subject includes one or both ankle joints. In some embodiments, the one or more sites of the subject includes one or both elbow joints. In some embodiments, the one or more sites of the subject includes one or both wrist joints. In some embodiments, the one or more sites of the subject includes one or more neck spine joints. In some embodiments, the one or more sites of the subject includes one or more back spine joints. In some embodiments, the one or more sites of the subject includes one or both shoulder joints. In some embodiments, the one or more sites of the subject includes one or both of hip joints. In some embodiments, the one or more sites of the subject includes one or more of finger joints. In some embodiments, the one or more sites of the subject includes one or more of toe joints.
  • the one or more sites of the subject includes one or more head muscles, one or more neck muscles, one or more shoulder muscles, one or more upper arm muscles, one or more forearm muscles, one or more palm muscles, one or more finger muscles, one or more chest muscles, one or more abdomen muscles, one or more back muscles, one or more hip muscles, one or more thigh muscles, one or more calf muscles, one or more sole muscles, and/or one or more toe muscles.
  • the one or more sites of the subject includes one or more head muscles. In some embodiments, the one or more sites of the subject includes one or more neck muscles. In some embodiments, the one or more sites of the subject includes one or more shoulder muscles. In some embodiments, the one or more sites of the subject includes one or more upper arm muscles. In some embodiments, the one or more sites of the subject includes one or more forearm muscles. In some embodiments, the one or more sites of the subject includes one or more palm muscles. In some embodiments, the one or more sites of the subject includes one or more finger muscles. In some embodiments, the one or more sites of the subject includes one or more chest muscles. In some embodiments, the one or more sites of the subject includes one or more abdomen muscles.
  • the one or more sites of the subject includes one or more back muscles. In some embodiments, the one or more sites of the subject includes one or more hip muscles. In some embodiments, the one or more sites of the subject includes one or more thigh muscles. In some embodiments, the one or more sites of the subject includes one or more calf muscles. In some embodiments, the one or more sites of the subject includes one or more sole muscles. In some embodiments, the one or more sites of the subject includes one or more toe muscles.
  • the one or more sites of the subject includes one or more head bones, one or more neck spine bones, one or more shoulder bones, one or more upper arm bones, one or more forearm bones, one or more palm bones, one or more finger bones, one or more shoulder blade bones, one or more rib bones, one or more back spine bones, one or more hip bones, one or more thigh bones, one or more calf bones, one or more sole bones, and/or one or more toe bones.
  • the one or more sites of the subject includes one or more head bones. In some embodiments, the one or more sites of the subject includes one or more neck spine bones. In some embodiments, the one or more sites of the subject includes one or more shoulder bones. In some embodiments, the one or more sites of the subject includes one or more upper arm bones. In some embodiments, the one or more sites of the subject includes one or more forearm bones. In some embodiments, the one or more sites of the subject includes one or more palm bones. In some embodiments, the one or more sites of the subject includes one or more finger bones. In some embodiments, the one or more sites of the subject includes one or more shoulder blade bones. In some embodiments, the one or more sites of the subject includes one or more rib bones.
  • the one or more sites of the subject includes one or more back spine bones. In some embodiments, the one or more sites of the subject includes one or more hip bones. In some embodiments, the one or more sites of the subject includes one or more thigh bones. In some embodiments, the one or more sites of the subject includes one or more calf bones. In some embodiments, the one or more sites of the subject includes one or more sole bones. In some embodiments, the one or more sites of the subject includes one or more toe bones.
  • the one or more sites of the subject includes one or more knee cartilages, one or more ankle cartilages, one or more elbow cartilages, one or more wrist cartilages, one or more neck spine cartilages, one or more back spine cartilages, one or more shoulder cartilages, one or more of hip cartilages, one or more of finger cartilages, and/or one or more of toe cartilages.
  • the one or more sites of the subject includes one or more knee cartilages. In some embodiments, the one or more sites of the subject includes one or more ankle cartilages. In some embodiments, the one or more sites of the subject includes one or more elbow cartilages. In some embodiments, the one or more sites of the subject includes one or more wrist cartilages. In some embodiments, the one or more sites of the subject includes one or more neck spine cartilages. In some embodiments, the one or more sites of the subject includes one or more back spine cartilages. In some embodiments, the one or more sites of the subject includes one or more shoulder cartilages. In some embodiments, the one or more sites of the subject includes one or more of hip cartilages. In some embodiments, the one or more sites of the subject includes one or more of finger cartilages. In some embodiments, the one or more sites of the subject includes one or more of toe cartilages.
  • one of the one or more sites of the subject is one joint, one muscle, one bone, one cartilage, or one area of soft tissues. In some embodiments, one of the one or more sites of the subject is one joint. In some embodiments, one of the one or more sites of the subject is one muscle. In some embodiments, one of the one or more sites of the subject is one bone. In some embodiments, one of the one or more sites of the subject is one cartilage. In some embodiments, one of the one or more sites of the subject is one area of soft tissues.
  • one of the one or more sites of the subject is one joint, one muscle, one bone, one cartilage, or one area of soft tissues suffering from, at risk of suffering from, or potentially capable of suffering from pain.
  • one of the one or more sites of the subject is one joint suffering from, at risk of suffering from, or potentially capable of suffering from joint pain.
  • one of the one or more sites of the subject is one muscles suffering from, at risk of suffering from, or potentially capable of suffering from muscle pain.
  • one of the one or more sites of the subject is one bone suffering from, at risk of suffering from, or potentially capable of suffering from bone pain.
  • one of the one or more sites of the subject is one cartilage suffering from, at risk of suffering from, or potentially capable of suffering from cartilage pain. In some embodiments, one of the one or more sites of the subject is one area of soft tissues suffering from, at risk of suffering from, or potentially capable of suffering from soft tissue pain.
  • one of the one or more sites of the subject is one joint, one muscle, one bone, one cartilage, or one area of soft tissues suffering from, at risk of suffering from, or potentially capable of suffering from inflammation. In some embodiments, one of the one or more sites of the subject is one joint suffering from, at risk of suffering from, or potentially capable of suffering from arthritis. In some embodiments, one of the one or more sites of the subject is one joint suffering from, at risk of suffering from, or potentially capable of suffering from osteoarthritis.
  • each of the sites of the subject is any one joint suffering from, at risk of suffering from, or potentially capable of suffering from osteoarthritis.
  • any one of the sites of the subject are selected from any one in a group consisting of knees, ankles, elbows, wrists, shoulders, hips, fingers, and toes.
  • each of the sites of the subject are selected from a group consisting of knees, ankles, thighs, calves, soles, elbows, wrists, upper arms, forearms, palms, neck, back, shoulders, hips, chest, abdomen, hips, fingers, and toes.
  • one of the one or more sites of the subject is one head, one knee, one ankle, one thigh, one calf, one sole, one elbow, one wrist, one upper arm, one forearm, one palm, one neck, one back, one shoulder, one side of chest, one abdomen, one side of hips, one finger, or one toe.
  • one of the one or more sites of the subject is one head. In some embodiments, one of the one or more sites of the subject is one knee. In some embodiments, one of the one or more sites of the subject is one ankle. In some embodiments, one of the one or more sites of the subject is one thigh. In some embodiments, one of the one or more sites of the subject is one calf. In some embodiments, one of the one or more sites of the subject is one sole. In some embodiments, one of the one or more sites of the subject is one elbow. In some embodiments, one of the one or more sites of the subject is one wrist. In some embodiments, one of the one or more sites of the subject is one upper arm.
  • one of the one or more sites of the subject is one forearm. In some embodiments, one of the one or more sites of the subject is one palm. In some embodiments, one of the one or more sites of the subject is one neck. In some embodiments, one of the one or more sites of the subject is one back. In some embodiments, one of the one or more sites of the subject is one shoulder. In some embodiments, one of the one or more sites of the subject is one side of chest. In some embodiments, one of the one or more sites of the subject is one abdomen. In some embodiments, one of the one or more sites of the subject is one side of hips. In some embodiments, one of the one or more sites of the subject is one finger. In some embodiments, one of the one or more sites of the subject is one toe.
  • one of the one or more sites of the subject is one knee joint, one ankle joint, one elbow joint, one wrist joint, one neck spine joint, one back spine joint, one shoulder joint, one hip joint, one finger joint, or one toe joint.
  • one of the one or more sites of the subject is one head muscle, one neck muscle, one shoulder muscle, one upper arm muscle, one forearm muscle, one palm muscle, one finger muscle, one chest muscle, one abdomen muscle, one back muscle, one hip muscle, one thigh muscle, one calf muscle, one sole muscle, or one toe muscle.
  • one of the one or more sites of the subject is one head muscle. In some embodiments, one of the one or more sites of the subject is one neck muscle. In some embodiments, one of the one or more sites of the subject is one shoulder muscle. In some embodiments, one of the one or more sites of the subject is one upper arm muscle. In some embodiments, one of the one or more sites of the subject is one forearm muscle. In some embodiments, one of the one or more sites of the subject is one palm muscle. In some embodiments, one of the one or more sites of the subject is one finger muscle. In some embodiments, one of the one or more sites of the subject is one chest muscle. In some embodiments, one of the one or more sites of the subject is one abdomen muscle.
  • one of the one or more sites of the subject is one back muscle. In some embodiments, one of the one or more sites of the subject is one hip muscle. In some embodiments, one of the one or more sites of the subject is one thigh muscle. In some embodiments, one of the one or more sites of the subject is one calf muscle. In some embodiments, one of the one or more sites of the subject is one sole muscle. In some embodiments, one of the one or more sites of the subject is one toe muscle.
  • one of the one or more sites of the subject is one head bone, one neck spine bone, one shoulder bone, one upper arm bone, one forearm bone, one palm bone, one finger bone, one shoulder blade bone, one rib bone, one back spine bone, one hip bone, one thigh bone, one calf bone, one sole bone, or one toe bone.
  • one of the one or more sites of the subject is one head bone. In some embodiments, one of the one or more sites of the subject is one neck spine bone. In some embodiments, one of the one or more sites of the subject is one shoulder bone. In some embodiments, one of the one or more sites of the subject is one upper arm bone. In some embodiments, one of the one or more sites of the subject is one forearm bone. In some embodiments, one of the one or more sites of the subject is one palm bone. In some embodiments, one of the one or more sites of the subject is one finger bone. In some embodiments, one of the one or more sites of the subject is one shoulder blade bone. In some embodiments, one of the one or more sites of the subject is one rib bone.
  • one of the one or more sites of the subject is one back spine bone. In some embodiments, one of the one or more sites of the subject is one hip bone. In some embodiments, one of the one or more sites of the subject is one thigh bone. In some embodiments, one of the one or more sites of the subject is one calf bone. In some embodiments, one of the one or more sites of the subject is one sole bone. In some embodiments, one of the one or more sites of the subject is or one toe bone.
  • one of the one or more sites of the subject is one knee cartilage, one ankle cartilage, one elbow cartilage, one wrist cartilage, one neck spine cartilage, one back spine cartilage, one shoulder cartilage, one hips cartilage, one finger cartilage, or one toe cartilage.
  • one of the one or more sites of the subject is one knee cartilage. In some embodiments, one of the one or more sites of the subject is one ankle cartilage. In some embodiments, one of the one or more sites of the subject is one elbow cartilage. In some embodiments, one of the one or more sites of the subject is one wrist cartilage. In some embodiments, one of the one or more sites of the subject is one neck spine cartilage. In some embodiments, one of the one or more sites of the subject is one back spine cartilage. In some embodiments, one of the one or more sites of the subject is one shoulder cartilage. In some embodiments, one of the one or more sites of the subject is one hips cartilage. In some embodiments, one of the one or more sites of the subject is one finger cartilage. In some embodiments, one of the one or more sites of the subject is or one toe cartilage.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or both knees, one or both ankles, one or both elbows, one or both wrists, one or more neck spines, one or more back spines, one or both shoulders, a side of hips, one or more of fingers, one or more of toes, and one or more areas of soft tissues.
  • a site of the subject includes one or more surfaces.
  • a site of the subject includes the medial surface, the lateral surface, the front surface and/or the back surface thereof.
  • the site includes the medial surface thereof.
  • the site includes the lateral surface thereof.
  • the site includes the front surface thereof.
  • the site includes the back surface thereof.
  • the site includes the medial surface and the lateral surface thereof.
  • the site includes the front surface and the back surface thereof.
  • the site includes the medial surface, the front surface and the back surface thereof.
  • the site includes the lateral surface, the front surface and the back surface thereof.
  • the site includes the medial surface, the front surface and the lateral surface thereof. In some embodiments, the site includes the lateral surface, the front surface and the medial surface thereof. In some embodiments, the site includes the medial surface, the lateral surface, the front surface and the back surface thereof.
  • a site of the subject includes one or more surfaces of the joint, or around, or close to the joint. In some embodiments, a site of the subject includes one or more surfaces of the joint. In some embodiments, a site of the subject includes one or more surfaces around or close to the muscle. In some embodiments, a site of the subject includes one or more surfaces around or close to the bone. In some embodiments, a site of the subject includes one or more surfaces around or close to the cartilage.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the medial surface, the lateral surface, the front surface and/or the back surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the medial surface of the knee or knees.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the lateral surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the front surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the back surface of the knee or knees.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the medial surface and the lateral surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the front surface and the back surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the medial surface, the front surface and the back surface of the knee or knees.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the lateral surface, the front surface and the back surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the medial surface, the front surface and the lateral surface of the knee or knees.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the lateral surface, the front surface and the medial surface of the knee or knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the medial surface, the lateral surface, the front surface and the back surface of the knee or knees.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to one or both elbow joint. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to one or both wrist joints. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to one or more of neck spine joints.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface close to one or more back spine joints. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to one or both shoulder joints. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to one or both hip joints.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to the joints of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fingers.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to the surface around and/or close to the joints of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 toes.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to one or both elbow joint. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to one or both wrist joints. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to one or more neck spine joints.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces close to one or more back spine joints. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to one or both shoulder joints. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to one or both hip joints.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to the joints of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fingers.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered to one or more surfaces around and/or close to the joints of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 toes.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on the administered area.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both knees, one or both ankles, one or both elbows, one or both wrists, neck, back, one or both shoulders, one side or both sides of hips, one or more of fingers, and/or one or more of toes.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both knees. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both ankles. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both elbows.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both wrists. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain the neck. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on the back.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both shoulders. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or both side of hips. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or more of fingers. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered until no pain on one or more of toes.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered by a transdermal administration.
  • 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered by a dosage form selected from one or more of transdermal patch, cream, foam, gel, lotion, ointment, paste, powder, shake lotion, solid, sponge, tape, tinkture, vapor, injection, drops, rinces, spray, and solution.
  • 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered by a dosage form selected from one or more of one or more of transdermal drops, rinces and spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered by a spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered by a spray for joint suffering from osteoarthritis.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered by a drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered by a drop for joint suffering from osteoarthritis.
  • 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is topically administered by a dosage form including one or more unit doses.
  • the dosage from is selected from one or more of transdermal patch, cream, foam, gel, lotion, ointment, paste, powder, shake lotion, solid, sponge, tape, tinkture, vapor, injection, drops, rinces, spray, and solution, and the dosage form including one or more unit doses.
  • the dosage form is spray application. In some embodiments, the dosage form is a spray for joint suffering from osteoarthritis. In some embodiments, the dosage form is a plurality times of sprays, and the each one of the unit doses is once spray in the plurality of sprays. In some embodiments, the dosage form is a plurality of patches, and the each one of the unit doses is a patch in the plurality of patches. In some embodiments, the dosage form is drop application. In some embodiments, the dosage form is a drop for joint suffering from osteoarthritis. In some embodiments, the dosage form is a plurality times of drops, and the each one of the unit doses is once drop in the plurality of drops.
  • a composition comprising 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered to the subject.
  • the unit dose comprising a composition comprising 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered to the subject.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is topically administered as dissolving in a solution.
  • the composition is a solution.
  • the composition is an alcohol solution.
  • the composition is an acetone solution.
  • the composition is a dimethyl sulfoxide solution.
  • the composition is an alcohol water solution.
  • the composition is an acetone water solution.
  • the composition is a dimethyl sulfoxide water solution.
  • the composition is a solution including water and alcohol, wherein said alcohol is at least one, two or more selected from a group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, active amyl alcohol, tert-amyl alcohol, neopentyl alcohol, methyl n-propyl carbinol, methyl isopropyl carbinol and 3-pentanol.
  • the composition is a solution including water, and ethanol and/or isopropanol.
  • the composition is an ethanol water solution. In some embodiments, the composition is 0%to 50% (v/v) ethanol water solution. In some embodiments, the composition is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%or 50% (v/v) ethanol water solution. In some embodiments, the composition is 25% (v/v) ethanol water solution.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 10 mg/mL to about 200 mg/mL, in particular 10 mg/mL to 200 mg/mL. In some embodiments, in the composition, the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 30 mg/mL to about 100 mg/mL, in particular 30 mg/mL to 100 mg/mL.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 50 mg/mL to about 80 mg/mL, in particular 50 mg/mL to 80 mg/mL. In some embodiments, in the composition, the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 60 mg/mL to about 75 mg/mL, in particular 60 mg/mL to 75 mg/mL.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 70 mg/mL to about 72 mg/mL, in particular 70 mg/mL to 72 mg/mL. In some embodiments, in the composition, the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 70 mg/mL, in particular 70 mg/mL.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 72 mg/mL, in particular 72 mg/mL.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is selected from a group consisting of 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 61 mg/mL, 62 mg/mL, 63 mg/mL, 64 mg/mL, 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL, 69 mg/mL, 70 mg/mL, 71 mg/mL, 72 mg/mL, 73 mg/mL, 74 mg/mL, 75 mg/mL, 76 mg/mL, 77 mg/mL, 78 mg/mL, 79 mg
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 10 mg/g to about 200 mg/g, in particular 10 mg/g to 200 mg/g. In some embodiments, in the composition, the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 30 mg/g to about 100 mg/g, in particular 30 mg/g to 100 mg/g.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 50 mg/g to about 80 mg/g, in particular 50 mg/g to 80 mg/g. In some embodiments, in the composition, the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 60 mg/g to about 75 mg/g, in particular 60 mg/g to 75 mg/g.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 70 mg/g to about 72 mg/g, in particular 70 mg/g to 72 mg/g. In some embodiments, in the composition, the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 70 mg/g, in particular 70 mg/g.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is about 72 mg/g, in particular 72 mg/g.
  • the concentration of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof is selected from a group consisting of 5 mg/g, 10 mg/g, 15 mg/g, 20 mg/g, 25 mg/g, 30 mg/g, 35 mg/g, 40 mg/g, 45 mg/g, 50 mg/g, 55 mg/g, 60 mg/g, 61 mg/g, 62 mg/g, 63 mg/g, 64 mg/g, 65 mg/g, 66 mg/g, 67 mg/g, 68 mg/g, 69 mg/g, 70 mg/g, 71 mg/g, 72 mg/g, 73 mg/g, 74 mg/g, 75 mg/g, 76 mg/g, 77 mg/g, 78 mg/g, 79 mg/g, 80 mg/g, 85 mg/g, 90 mg/g, 95 mg/g, 100 mg/g, 110 mg
  • the volume of the composition in the unit dose is about 0.01 mL to about 1 mL, in particular 0.01 mL to 1 mL. In some embodiments, the volume of the composition in the unit dose is about 0.03 mL to about 0.3 mL, in particular 0.03 mL to 0.3 mL. In some embodiments, the volume of the composition in the unit dose is about 0.05 mL to about 0.2 mL, in particular 0.05 mL to 0.2 mL. In some embodiments, the volume of the composition in the unit dose is about 0.05 mL to about 0.1 mL, in particular 0.05 mL to 0.1 mL.
  • the volume of the composition in the unit dose is about 0.07 mL, in particular 0.07 mL.
  • the volume of the composition in the unit dose is selected from a group consisting of 0.01 mL, 0.015 mL, 0.02 mL, 0.025 mL, 0.03 mL, 0.035 mL, 0.04 mL, 0.045 mL, 0.05 mL, 0.0525 mL, 0.055 mL, 0.0575 mL, 0.06 mL, 0.0625 mL, 0.065 mL, 0.0675 mL, 0.07 mL, 0.0725 mL, 0.075 mL, 0.08 mL, 0.085 mL, 0.09 mL, 0.095 mL, 0.1 mL, 0.11 mL, 0.12 mL, 0.13 mL, 0.14 mL, 0.15 mL, 0.16 mL, 0.18 mL, 0.2
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per unit dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per unit dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1 mg to about 10 mg, in particular 1 mg to 10 mg per unit dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per unit dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 2 mg to about 6 mg, in particular 2 mg to 6 mg per unit dose.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 3 mg to about 5 mg, in particular 3 mg to 5 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per unit dose. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4.5 mg, in particular 4.5 mg per unit dose.
  • one or more of the unit doses is topically administered to the subject in a single dose, per site, wherein the one or more of unit doses are selected from a group consisting of 1 unit dose, 2 unit doses, 3 unit doses, 4 unit doses, 5 unit doses, 6 unit doses, 7 unit doses, 8 unit doses, 9 unit doses, 10 unit doses, 11 unit doses, 12 unit doses, 13 unit doses, 14 unit doses, 15 unit doses, 16 unit doses, 17 unit doses, 18 unit doses, 19 unit doses, and 20 unit doses.
  • 1-10 unit doses is topically administered to the subject in a single dose, per site.
  • 1-8 unit doses is topically administered to the subject in a single dose, per site.
  • 2-8 unit doses is topically administered to the subject in a single dose, per site.
  • 2-4 unit doses is topically administered to the subject in a single dose, per site.
  • 4-8 unit doses is topically administered to the subject in a single dose, per site.
  • 1 unit dose is topically administered to the subject in a single dose, per site.
  • 2 unit doses is topically administered to the subject in a single dose, per site.
  • 3 unit doses is topically administered to the subject in a single dose, per site.
  • 4 unit doses is topically administered to the subject in a single dose, per site. In some embodiments, 5 unit doses is topically administered to the subject in a single dose, per site. In some embodiments, 6 unit doses is topically administered to the subject in a single dose, per site. In some embodiments, 7 unit doses is topically administered to the subject in a single dose, per site. In some embodiments, 8 unit doses is topically administered to the subject in a single dose, per site. In some embodiments, 9 unit doses is topically administered to the subject in a single dose, per site. In some embodiments, 10 unit doses is topically administered to the subject in a single dose, per site.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof, per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 1 mg to about 10 mg, in particular 1 mg to 10 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 2 mg to about 6 mg, in particular 2 mg to 6 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 3 mg to about 5 mg, in particular 3 mg to 5 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a spray capable of spraying about 4.5 mg, in particular 4.5 mg per spray.
  • the dosage form is a spray.
  • the volume of the composition per spray is about 0.01 mL to about 1 mL, in particular 0.01 mL to 1 mL.
  • the volume of the composition per spray is about 0.03 mL to about 0.3 mL, in particular 0.03 mL to 0.3 mL.
  • the volume of the composition per spray is about 0.05 mL to about 0.2 mL, in particular 0.05 mL to 0.2 mL.
  • the volume of the composition per spray is about 0.05 mL to about 0.1 mL, in particular 0.05 mL to 0.1 mL.
  • the volume of the composition per spray is about 0.0625 mL, in particular 0.0625 mL.
  • the volume of the composition per spray is selected from a group consisting of 0.01 mL, 0.015 mL, 0.02 mL, 0.025 mL, 0.03 mL, 0.035 mL, 0.04 mL, 0.045 mL, 0.05 mL, 0.0525 mL, 0.055 mL, 0.0575 mL, 0.06 mL, 0.0625 mL, 0.065 mL, 0.0675 mL, 0.07 mL, 0.0725 mL, 0.075 mL, 0.08 mL, 0.085 mL, 0.09 mL, 0.095 mL, 0.1 mL, 0.11 mL, 0.12 mL, 0.13 mL, 0.14 mL, 0.15 mL, 0.16 mL, 0.18 mL, 0.2 mL, 0.09 mL
  • the dosage form is a spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per spray. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per spray. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1 mg to about 10 mg, in particular 1 mg to 10 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per spray. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per spray. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 2 mg to about 6 mg, in particular 2 mg to 6 mg per spray.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 3 mg to about 5 mg, in particular 3 mg to 5 mg per spray. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per spray. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4.5 mg, in particular 4.5 mg per spray.
  • the drug strength per spray is between 0.1 mg to 75 mg of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per spray is about 1 mg to about 20 mg, in particular 1 mg to 20 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per spray is about 1.2 mg to about 10 mg, in particular 1.2 mg to 10 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • the drug strength per spray is about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per spray is about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per spray is about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per spray is about 4 mg to about 4.5 mg, in particular 4 mg to 4.5 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof, per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 1 mg to about 10 mg, in particular 1 mg to 10 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 2 mg to about 6 mg, in particular 2 mg to 6 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 3 mg to about 5 mg, in particular 3 mg to 5 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a drop capable of dropping about 4.5 mg, in particular 4.5 mg per drop.
  • the dosage form is a drop.
  • the volume of the composition per drop is about 0.01 mL to about 1 mL, in particular 0.01 mL to 1 mL.
  • the volume of the composition per drop is about 0.03 mL to about 0.3 mL, in particular 0.03 mL to 0.3 mL.
  • the volume of the composition per drop is about 0.05 mL to about 0.2 mL, in particular 0.05 mL to 0.2 mL.
  • the volume of the composition per drop is about 0.05 mL to about 0.1 mL, in particular 0.05 mL to 0.1 mL.
  • the volume of the composition per drop is about 0.0625 mL, in particular 0.0625 mL. In some embodiments, the volume of the composition per drop is selected from a group consisting of 0.01 mL, 0.015 mL, 0.02 mL, 0.025 mL, 0.03 mL, 0.035 mL, 0.04 mL, 0.045 mL, 0.05 mL, 0.0525 mL, 0.055 mL, 0.0575 mL, 0.06 mL, 0.0625 mL, 0.065 mL, 0.0675 mL, 0.07 mL, 0.0725 mL, 0.075 mL, 0.08 mL, 0.085 mL, 0.09 mL, 0.095 mL, 0.1 mL, 0.11 mL, 0.12 mL, 0.13 mL, 0.14 mL, 0.15 mL, 0.16 mL, 0.18 mL, 0.2 mL, 0.01
  • the dosage form is a drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1 mg to about 10 mg, in particular 1 mg to 10 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 2 mg to about 6 mg, in particular 2 mg to 6 mg per drop.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 3 mg to about 5 mg, in particular 3 mg to 5 mg per drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per drop. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4.5 mg, in particular 4.5 mg per drop.
  • the drug strength per drop is between 0.1 mg to 75 mg of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per drop is about 1 mg to about 20 mg, in particular 1 mg to 20 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per drop is about 1.2 mg to about 10 mg, in particular 1.2 mg to 10 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • the drug strength per drop is about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per drop is about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per drop is about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per drop is about 4 mg to about 4.5 mg, in particular 4 mg to 4.5 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof, per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 1 mg to about 10 mg, in particular 1 mg to 10 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 2 mg to about 6 mg, in particular 2 mg to 6 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 3 mg to about 5 mg, in particular 3 mg to 5 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered by a patch capable of administering about 4.5 mg, in particular 4.5 mg per patch.
  • the dosage form is a patch.
  • the volume of the composition per patch is about 0.01 mL to about 1 mL, in particular 0.01 mL to 1 mL.
  • the volume of the composition per patch is about 0.03 mL to about 0.3 mL, in particular 0.03 mL to 0.3 mL.
  • the volume of the composition per patch is about 0.05 mL to about 0.2 mL, in particular 0.05 mL to 0.2 mL.
  • the volume of the composition per patch is about 0.05 mL to about 0.1 mL, in particular 0.05 mL to 0.1 mL.
  • the volume of the composition per patch is about 0.0625 mL, in particular 0.0625 mL.
  • the volume of the composition per patch is selected from a group consisting of 0.01 mL, 0.015 mL, 0.02 mL, 0.025 mL, 0.03 mL, 0.035 mL, 0.04 mL, 0.045 mL, 0.05 mL, 0.0525 mL, 0.055 mL, 0.0575 mL, 0.06 mL, 0.0625 mL, 0.065 mL, 0.0675 mL, 0.07 mL, 0.0725 mL, 0.075 mL, 0.08 mL, 0.085 mL, 0.09 mL, 0.095 mL, 0.1 mL, 0.11 mL, 0.12 mL, 0.13 mL, 0.14 mL, 0.15 mL, 0.16 mL, 0.18 mL, 0.2 mL, 0.09 mL
  • the dosage form is a patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg per patch. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg per patch. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1 mg to about 10 mg, in particular 1 mg to 10 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg per patch. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg per patch. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 2 mg to about 6 mg, in particular 2 mg to 6 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 3 mg to about 5 mg, in particular 3 mg to 5 mg per patch. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg per patch. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount of about 4.5 mg, in particular 4.5 mg per patch.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered in an amount, administered by a spray in an amount, administered by a spray capable of administering in an amount, administered by a drop in an amount, administered by a drop capable of administering in an amount, administered by a patch in an amount, and/or administered a patch capable of administering in an amount, selected from a group consisting of 0.1 mg, 0.2 mg, 0.3 mg, 0.4mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.05 mg, 2.1 mg, 2.15 mg, 2.2 mg, 2.25 mg, 2.3 mg, 2.35 mg, 2.4 mg, 2.
  • the drug strength per patch is between 0.1 mg to 75 mg of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per patch is about 1 mg to about 20 mg, in particular 1 mg to 20 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per patch is about 1.2 mg to about 10 mg, in particular 1.2 mg to 10 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • the drug strength per patch is about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per patch is about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per patch is about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate. In some embodiments, the drug strength per patch is about 4 mg to about 4.5 mg, in particular 4 mg to 4.5 mg, of free base of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • the drug strength per spray, per drop and/or per patch is selected from a group consisting of 0.1 mg, 0.2 mg, 0.3 mg, 0.4mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.05 mg, 2.1 mg, 2.15 mg, 2.2 mg, 2.25 mg, 2.3 mg, 2.35 mg, 2.4 mg, 2.45 mg, 2.5 mg, 2.55 mg, 2.6 mg, 2.65 mg, 2.7 mg, 2.75 mg, 2.8 mg, 2.85 mg, 2.9 mg, 2.95 mg, 3 mg, 3.05 mg, 3.1 mg, 3.15 mg, 3.2 mg, 3.25 mg, 3.3 mg, 3.35 mg, 3.4 mg, 3.45 mg, 3.5 mg, 3.55 mg, 3.6 mg, 3.65 mg,
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once, twice, three times, four times, five times or six times a day, or once every one, two, three, four, five, six, or seven days.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once, twice, three times, four times, five times, six times, seven times or eight times a day. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once a day. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered twice a day.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered three times a day. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered four a day. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered five times a day.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered six times a day. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered seven times a day. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered eight times a day.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every hour or once every 4 to 16 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every hour or once every 8 to 12 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every hour or once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every hour or once every 12 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every hour. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 2 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 3 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 4 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 5 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 6 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 7 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 8 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 9 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 10 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 11 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 12 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 13 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 14 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 15 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 16 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 17 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 18 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 19 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 20 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 2 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 21 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 22 hours. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once 23 hours.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every one, two, three, four, five, six, or seven days. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered daily. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered intermittently.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every two days. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every three days. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every four days. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every five days.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every six days. In some embodiments, 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or pharmaceutically acceptable salts thereof is administered once every week.
  • the topical administration is administered for 1 day to lifetime. In some embodiments, the topical administration is administered for 7 to 365 consecutive or non-consecutive days. In some embodiments, the topical administration is administered for 7 to 98 consecutive or non-consecutive days. In some embodiments, the topical administration is administered for 14 to 91 consecutive or non-consecutive days. In some embodiments, the topical administration is administered for 14 to 84 consecutive or non-consecutive days. In some embodiments, the topical administration is administered for 28 to 84 consecutive or non-consecutive days. In some embodiments, the topical administration is administered for 56 to 84 consecutive or non-consecutive days.
  • the topical administration is administered for 7 to 98 consecutive days. In some embodiments, the topical administration is administered for 14 to 91 consecutive days. In some embodiments, the topical administration is administered for 14 to 84 consecutive days. In some embodiments, the topical administration is administered for 28 to 84 consecutive days. In some embodiments, the topical administration is administered for 56 to 84 consecutive days.
  • the topical administration is administered for at least one or more consecutive days or non-consecutive days, particularly a number of said one or more consecutive or non-consecutive days is selected from a group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100
  • the device of the present disclosure includes a dosage form selected from one or more of transdermal patch, cream, foam, gel, lotion, ointment, paste, powder, shake lotion, solid, sponge, tape, tinkture, vapor, injection, drops, rinces, spray, and solution.
  • the device of the present disclosure includes a dosage form selected from transdermal solutions, including one or more of transdermal drops, rinces and spray.
  • the device of the present disclosure is a device capable of administrating about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 1 mg to about 10 mg, in particular 1 mg to 10 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device of the present disclosure is a device capable of administrating about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device is a device capable of administrating about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device is a device capable of administrating about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose. In some embodiments, the device is a device capable of administrating about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device is a device capable of administrating about 4.375 mg to about 4.5 mg, in particular 4.375 mg to 4.5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each dose.
  • the device is a spray capable of spraying about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 0.8 mg to about 12 mg, in particular 0.7 mg to 12 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 1 mg to about 10 mg, in particular 0.1 mg to 10 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray capable of spraying about 4.375 mg to about 4.5 mg, in particular 4.375 mg to 4.5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each spray.
  • the device is a spray including a nozzle, the nozzle sprays about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 0.8 mg to about 12 mg, in particular 0.8 mg to 12 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 1 mg to about 10 mg, in particular 1 mg to 10 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 4 mg to about 8 mg, in particular 4 mg to 8 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a spray including a nozzle, the nozzle sprays about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the spray of the present disclosure is a spray including a nozzle, the nozzle sprays about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each time of pressing the nozzle.
  • the device is a drop capable of dropping about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 0.8 mg to about 12 mg, in particular 0.7 mg to 12 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 1 mg to about 10 mg, in particular 0.1 mg to 10 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop. In some embodiments, the device is a drop capable of dropping about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a drop capable of dropping about 4.375 mg to about 4.5 mg, in particular 4.375 mg to 4.5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each drop.
  • the device is a device capable of administrating in an amount, a spray including an amount, a spray including a nozzle spraying in an amount, or a drop including an amount, selected from a group consisting of 0.1 mg, 0.2 mg, 0.3 mg, 0.4mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.05 mg, 2.1 mg, 2.15 mg, 2.2 mg, 2.25 mg, 2.3 mg, 2.35 mg, 2.4 mg, 2.45 mg, 2.5 mg, 2.55 mg, 2.6 mg, 2.65 mg, 2.7 mg, 2.75 mg, 2.8 mg, 2.85 mg, 2.9 mg, 2.95 mg, 3 mg, 3.05 mg, 3.1 mg, 3.15 mg, 3.2 mg, 3.25 mg, 3.3
  • the device is a patch capable of administering about 0.1 mg to about 20 mg, in particular 0.1 mg to 20 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 0.2 mg to about 18 mg, in particular 0.2 mg to 18 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 0.4 mg to about 16 mg, in particular 0.4 mg to 16 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 0.6 mg to about 14 mg, in particular 0.6 mg to 14 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 0.8 mg to about 12 mg, in particular 0.7 mg to 12 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 1 mg to about 10 mg, in particular 0.1 mg to 10 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 1.2 mg to about 9 mg, in particular 1.2 mg to 9 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 1.5 mg to about 8 mg, in particular 1.5 mg to 8 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 1.8 mg to about 7 mg, in particular 1.8 mg to 7 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 2 mg to about 6 mg, in particular 2 mg to 6 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 3 mg to about 5 mg, in particular 3 mg to 5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 4 mg to about 4.75 mg, in particular 4 mg to 4.75 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch capable of administering about 4.375 mg to about 4.5 mg, in particular 4.375 mg to 4.5 mg, of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or pharmaceutically acceptable salts thereof in each patch.
  • the device is a patch including an amount selected from a group consisting of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.05 mg, 2.1 mg, 2.15 mg, 2.2 mg, 2.25 mg, 2.3 mg, 2.35 mg, 2.4 mg, 2.45 mg, 2.5 mg, 2.55 mg, 2.6 mg, 2.65 mg, 2.7 mg, 2.75 mg, 2.8 mg, 2.85 mg, 2.9 mg, 2.95 mg, 3 mg, 3.05 mg, 3.1 mg, 3.15 mg, 3.2 mg, 3.25 mg, 3.3 mg, 3.35 mg, 3.4 mg, 3.45 mg, 3.5 mg, 3.55 mg, 3.6 mg, 3.65 mg, 3.7 mg, 3.
  • composition including 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is presented as the table below.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the medial surface or the lateral surface, or the front surface or the back surface of the knee, once per day until no pain on the knee.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the medial surface or the lateral surface, or the front surface or the back surface of the knee, BID, until no pain on the knee.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the ankle joint, once per day until no pain on the ankle.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the ankle joint, BID, until no pain on the ankle.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the elbow joint, once per day until no pain on the elbow.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the elbow joint, BID until no pain on the elbow.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the wrist joint, once per day until no pain on the wrist.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the wrist joint, BID until no pain on the wrist.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, once per day until no pain on the shoulder.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, BID until no pain on the shoulder.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, once per day until no pain on the hip joint .
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, BID until no pain on the hip.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the finger joints, once per day until no pain on the fingers.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the finger joints, BID until no pain on the fingers
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the toe joints, once per day until no pain on the toes.
  • a subject will spray one spray (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the toe joints, BID until no pain on the toes.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the knee: one spray to the medial surface and one spray to the lateral surface of the knee, once per day until no pain on the knee.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the knee: one spray to the medial surface and one spray to the lateral surface of the knee, BID, until no pain on the knee.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the ankle joint, each spray to a different skin area, once per day until no pain on the ankle.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the ankle joint, BID, each spray to a different skin area, until no pain on the ankle.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the elbow joint, each spray to a different skin area, once per day until no pain on the elbow.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the elbow joint, each spray to a different skin area, BID until no pain on the elbow.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the wrist joint, once per day until no pain on the wrist.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the wrist joint, each spray to a different skin area, BID until no pain on the wrist.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, each spray to a different skin area, once per day until no pain on the shoulder.
  • a subject will spray one spray (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, each spray to a different skin area, BID until no pain on the shoulder.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, each spray to a different skin area, once per day until no pain on the hip joint .
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, each spray to a different skin area, BID until no pain on the hip.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the finger joints, each spray to a different skin area, once per day until no pain on the fingers.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the finger joints, BID until no pain on the fingers
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the toe joints, each spray to a different skin area, once per day until no pain on the toes.
  • a subject will spray two sprays (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the toe joints, each spray to a different skin area, BID until no pain on the toes.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to around of the knee: one spray to the medial surface, one spray to the lateral surface, one spray the front surface, and one spray the back surface of the knee, once per day until no pain on the knee.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to around of the knee: one spray to the medial surface, one spray to the lateral surface, one spray the front surface, and one spray the back surface of the knee, BID, until no pain on the knee.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the ankle joint, each spray to a different skin area, once per day until no pain on the ankle.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the ankle joint, each spray to a different skin area, BID, until no pain on the ankle.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the elbow joint, each spray to a different skin area, once per day until no pain on the elbow.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the elbow joint, each spray to a different skin area, BID until no pain on the elbow.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the wrist joint, each spray to a different skin area, once per day until no pain on the wrist.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the wrist joint, each spray to a different skin area, BID until no pain on the wrist.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, each spray to a different skin area, once per day until no pain on the shoulder.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, each spray to a different skin area, BID until no pain on the shoulder.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, once per day until no pain on the hip joint.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, each spray to a different skin area, BID until no pain on the hip.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the finger joints, each spray to a different skin area, once per day until no pain on the fingers.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the finger joints, each spray to a different skin area, BID until no pain on the fingers.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the toe joints, each spray to a different skin area, once per day until no pain on the toes.
  • a subject will spray four sprays (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the toe joints, each spray to a different skin area, BID until no pain on the toes.
  • a subject will spray eight sprays (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, once per day until no pain on the shoulder.
  • a subject will spray eight sprays (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the shoulder joint, BID until no pain on the shoulder.
  • a subject will spray eight sprays (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, once per day until no pain on the hip.
  • a subject will spray eight sprays (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the hip joint, BID until no pain on the hip.
  • a subject will spray eight sprays (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the knee, once per day until no pain on the knee.
  • a subject will spray eight sprays (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate in 25%ethanol) of the drug solution to the surface around the knee, BID until no pain on the knee.
  • a battery of pharmacology and toxicology studies including a GLP acute dermal maximum tolerated dose study in rats, a GLP acute dermal maximum tolerated dose study in Beagle dogs, a non-GLP 14-day repeated dermal dose toxicity study in rats, a non-GLP 14-day repeated dermal dose toxicity study in Beagle dogs, a 28-day GLP repeated dermal dose toxicity and toxicokinetics study in rats with 14-day recovery, a 28-day GLP repeated dermal dose toxicity and toxicokinetics study in Beagle dogs with 14-day recovery, a GLP bacterial reverse mutation assay (Ames) , a GLP in vitro chromosome aberration assay in CHO-WBL Cells, a GLP in vivo bone marrow micronucleus assay in rats, a behavioral effects in rats using the functional observational battery, a rat respiratory safety pharmacology study, a cardiovascular telemetry study in the unrestrained conscious dog, a skin irritation study in rabbits,
  • a battery of safety pharmacology studies including behavioral effects in rats using the functional observational battery, a rat respiratory safety pharmacology study, a cardiovascular telemetry study in the unrestrained conscious dogs were completed.
  • the results of the safety pharmacology studies conducted are shown in Table 2.
  • the study results show 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate appeared to be safe and were generally well tolerated.
  • the study design incorporated staggered durations of single doses followed by 7 days of twice daily (b.i.d. ) doses of study drug for evaluation of safety and pharmacokinetics as overlapping dose cohorts. There were 2 parts to the study.
  • each cohort began with single dose administration of drug on Day 1 and serial blood sample collection for evaluation of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and its metabolite, ibuprofen, concentrations and pharmacokinetic (PK) analysis over the 120-hour post-dose period.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate was administered b.i.d. during Days 6-11, and a morning dose only was administered to Day 12.
  • Blood samples were collected for PK analysis over the 120-hour post-dose period following the Day 12 dose. Additionally, pre-dose blood samples were collected on Day 7 through Day 11 to evaluate steady-state status.
  • Part 2 of the study a separate cohort of ten subjects (eight subjects randomized to receive active drug and two subjects to receive placebo) received a 70 mg dose as spray application (70 mg is equivalent to 16 sprays) . The same study procedures were followed as described in Part 1.
  • serial blood samples were collected on Day 1 dose at the following time points: 0 (pre-dose) , 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96 and 120 hours post-dose.
  • serial blood samples were collected on Day 12 at the following time points: 0 (pre-dose) , 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96 and 120 hours post-dose.
  • AEs adverse events
  • vital signs blood pressure, pulse rate, respiratory rate and oral temperature
  • ECG resting 12-lead electrocardiogram
  • the duration of treatment for each subject was up to approximately 6 weeks, including a 21-day screening period and a 17-day treatment period.
  • the primary objective of this study was to evaluate the safety and tolerability of escalating single and multiple doses of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate administered as a topical application.
  • the secondary objectives of this study were to characterize the single and steady-state pharmacokinetics of escalating doses of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and ibuprofen as a topical application and to evaluate relative bioavailability of spray application vs. topical application of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • Safety Population all subjects who receive at least one dose of study drug and have at least one post-dose safety assessment.
  • PK Population all subjects who receive all planed doses of active study drug, have no major protocol deviations, and have sufficient pharmacokinetic data to obtain reliable estimates of the key pharmacokinetic variables.
  • Protocol deviations were identified prior to database lock and may have included but were not limited to significant violations of inclusion/exclusion criteria, noncompliance of the trial treatment taken, use of prohibited medications and not following clinical trial protocol procedures.
  • Pharmacokinetic variables were calculated for 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and ibuprofen from the plasma concentration data using standard, non-compartmental methods using WinNonlin (version 6.2.1) and actual elapsed times of blood collection.
  • Pharmacokinetic variables determined are displayed in Table 4. Pharmacokinetic parameters are listed by subjects and summarized by treatment using descriptive statistics.
  • Accumulation ratios of C max , C max0-12hr and AUCs (AUC 0-12hr and AUC inf ) (Day 12 vs. Day 1 or Day 12 vs. Day 6) were calculated for subjects in each cohort in Part 1 and for subjects in Part 2 for both 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and ibuprofen, and summarized by treatment using descriptive statistics.
  • the relative bioavailability of the single dose 70 mg topical application vs. 70 mg spray application was determined based on AUC tau , AUC inf and C max .
  • the 90%confidence intervals (CIs) on the ratio of topical application vs.spray application were calculated.
  • Y represents the PK parameter C max , AUC last , AUC inf , AUC inf following single 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate administration and e represents the error term.
  • Safety endpoints consist of all AEs, clinical laboratory test results, ECG, physical examination and vital sign assessments and skin irritation assessments.
  • Safety summaries are provided for all subjects in the safety population. Data from subjects in each cohort who received placebo treatment were pooled. AE data, clinical laboratory test results, ECG, skin irritation and vital signs data are presented descriptively using summary tables and listings. Change from baseline in vital signs, ECG and clinical laboratory results are presented descriptively using summary tables and listings. Physical examination findings are listed by subject.
  • sample size determination This was an early development study, and therefore no statistical considerations were involved in the sample size determination. It was expected that the sample size of 10 subjects (eight subjects receiving active drug and two subjects receiving placebo) in each cohort should be adequate for evaluation of tolerability and pharmacokinetic parameters in this single and multiple ascending dose study.
  • Postmenopausal defined as:
  • Nonsmoker defined as not having smoked or used any form of tobacco in more than 6 months before screening;
  • Body mass index (BMI) 19 to 30 kg/m 2 inclusive and body weight not less than 50 kg;
  • HIV human immunodeficiency virus
  • HBsAg hepatitis B surface antigen
  • hepatitis C antibody hepatitis C antibody
  • OTC over-the-counter
  • Appropriate measures include use of a condom and spermicide and, for female partners, use of an intrauterine device (IUD) , diaphragm with spermicide, oral contraceptives, injectable progesterone, progesterone subdermal implants, or a tubal ligation.
  • IUD intrauterine device
  • Subjects within each cohort were randomly assigned to receive 17.5 mg, 35 mg, 70 mg, 140 mg, and 280 mg of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate or matching placebo administered as a topical application (Part 1, Cohorts 1-5) or 70 mg of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionat or placebo administered as a spray (Part 2, Cohort 6) .
  • subjects were assigned to receive active treatment or placebo at a 4: 1 ratio. Treatments for each cohort are displayed in Table 5.
  • Doses were administered to Day 1 at approximately 0800 hours ⁇ 1 hour, on Day 6 through Day 11 at approximately 0800 hours ⁇ 1 hour and 2000 hours ⁇ 1 hour, and on Day 12 at approximately 0800 hours ⁇ 1 hour. All doses were administered by CRU personnel according to a Dosing Manual prepared prior to the start of the study and approved by the sponsor.
  • the mean concentration versus time profiles on Day 1 and Day 12 from time 0 to 120 hours post-dose for ibuprofen are displayed by treatment on a linear scale in Figure 8 and Figure 9, respectively, and on a semi-log scale in Figure 10 and Figure 11, respectively.
  • this data is displayed for Day 1 from time 0 to 48 hours post-dose in Figure 12, and from time 0 to 48 hours post-dose for Day 12 in Figure 13.
  • TEAE treatment-emergent AE
  • AE alanine aminotransferase
  • aspartate aminotransferase increased was reported for 1 (12.5%) subject each after receiving 70 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and 70 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate spray.
  • Samples for clinical laboratory safety tests were obtained at the screening visit, Day -1, Day 4, Day 13 and prior to discharge from the study on Day 17 or at early termination. Any clinical laboratory findings considered to be clinically significant were recorded as AEs.
  • BUN Blood urea nitrogen
  • AST creatinine
  • ALT alanine transaminase
  • GTT gamma-glutamyltransferase
  • LDH lactate dehydrogenase
  • Hematology hemoglobin, hematocrit, red blood cell (RBC) count, platelet count and white blood cell (WBC) count with differential.
  • Urinalysis pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, leukocytes, urobilinogen and microscopy.
  • Urine pregnancy test females only at screening, and admission on Day -1 and Day 5, on Day 13 and prior to discharge from the study on Day 17 or at early termination.
  • Alcohol and drugs of abuse screen (amphetamines, barbiturates, cocaine metabolites, benzodiazepines, cannabinoids, opiates, ethyl alcohol) at screening and admission on Day -1 and Day 5.
  • Hepatitis B surface antibodies HBsAb
  • hepatitis C antibodies anti-HIV antibodies at screening.
  • One subject received the first dose of 70 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate as a spray on 29 May 2013, began b.i.d. dosing on 03 June 2013, and had increased ALT and increased AST recorded as an AE on 10 June 2013 (Day 13) . Both AEs were considered by the investigator as mild in intensity, related to study drug, and these AEs resolved on 18 June 2013 (ALT) and 14 June 2013 (AST) .
  • Systolic and diastolic blood pressure (mmHg) and pulse rate (beats per minute) , respiratory rate (breaths per minute) and oral temperature (°C) were measured after at least 5 minutes at rest in the seated position at the screening visit, at admission on Day -1, Day 5 and Day 13, and prior to and 1 hour following each dose administration.
  • a physical examination was performed at the screening visit and on Day 13, or at early termination, and included assessment of the following body systems: general appearance, dermatological, head, eyes, ears, nose and throat, neck, lymph nodes, lungs, heart, abdomen, neurological and musculoskeletal.
  • a resting 12-lead ECG was recorded after at least 5 minutes of rest at the screening visit and on Day 13, or at early termination.
  • the ECG parameters recorded include ventricular rate (bpm) , PR interval (msec) , QRS duration (msec) , QT interval (msec) , and QTc interval (msec) .
  • QTc interval was calculated at the clinic using a formula internal to the ECG equipment (Mortara) .
  • Skin irritation due to study drug application was measured by a dermal response score of 0-7 assigned for each study drug application site prior to and 30 min following each dose administration. A score of 6 or 7 was considered a severe reaction. Pre-dose assessments during the multiple dosing served as the 12 hour post-dose assessment of the prior dose.
  • the study design incorporated staggered durations of single doses followed by 7 days of b.i.d. doses of study drug for evaluation of safety and pharmacokinetics as overlapping dose cohorts.
  • serial blood samples were collected on Day 1 dose at the following time points: 0 (pre-dose) , 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96 and 120 hours post-dose.
  • serial blood samples were collected on Day 12 at the following time points: 0 (pre-dose) , 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96 and 120 hours post-dose.
  • the 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate prodrug was rapidly absorbed following topical application, and was also rapidly converted to its active metabolite, ibuprofen, upon absorption. Steady-state was achieved following 5 days of b.i.d. dosing. Dose proportionality could not be formally demonstrated as topical doses of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate increased from 17.5 mg to 280 mg.
  • NSAID nonsteroidal anti-inflammatory drugs
  • Subjects taking nonsteroidal anti-inflammatory drugs (NSAID) or other analgesics may enroll in the trial, but will discontinue any analgesic therapy for the duration of the study, starting at least 4 days (or 5 half lives, whichever is longer) prior to administration of the first dose of study medication (i.e., for an analgesic washout period before Day 1) .
  • NSAID nonsteroidal anti-inflammatory drugs
  • Subjects will be allowed to take rescue medication (up to six 325 mg tablets [total of 1950 mg] of acetaminophen per day; provided by the Sponsor) for residual knee or other body pain starting 4 days (or 5 half lives, whichever is longer) prior to administration of the first dose of study medication except during the 24 hours prior to Baseline (Day 1) , Week 2, Week 4, Week 8, Week 12/end of study (EOS) , and Follow up assessments.
  • a subject After a Screening Period of up to 3 weeks and radiographic evaluation of the target knee joint space, a subject will be randomly assigned to 1 of 3 treatment groups in a 1: 1: 1 ratio with a 2: 1 ratio of active: placebo within each treatment group (ie, 2 subjects to active treatment and 1 subject to placebo) :
  • Each subject will receive study treatment for 12 weeks starting on Day 1. Qualified site personnel will contact subjects 1 week after the first administration of study medication to check if there are any issues with the spray bottles, administration of study medication, or adverse events (AEs) . Subjects will return to the site at 2, 4, 8, and 12 weeks of treatment for efficacy and safety assessments as indicated in the study flow chart. The Week 12 visit will be the EOS visit. On the final day of dose administration (Week 12/EOS visit) , subjects will receive 1 dose of study medication in the morning only; radiographs will be performed to assess changes in the target knee joint space. Subjects will have a Follow up visit approximately 7 days after the Week 12/EOS visit.
  • Subjects will record the following information in a Daily Diary starting at Screening: the amount of knee pain in the target knee while walking during the preceding 24 hours (using a 100 mm visual analog scale [VAS] ) , the times and number of sprays for each administration of study medication, the times when the subject washes his/her knees and/or takes a shower, the number of tablets of rescue medication taken that day and the times taken, the reason for taking the rescue medication (e.g., knee pain, headache, low back pain) , any other concomitant medications taken that day, and any AEs occurring that day.
  • VAS visual analog scale
  • the VAS version of the WOMAC will be used for the Primary and Secondary Efficacy Endpoints. Efficacy endpoints will be assessed at Screening and Baseline (Day 1) and at the Week 2, Week 4, Week 8, and Week 12/EOS visits.
  • PK blood samples will be collected predose and at 1, 3, 6, 8, 10, and 12 hours postdose.
  • subjects in the PK subgroup will be confined to the study site for approximately 36 hours after the last dose of study medication so that PK blood samples can be collected predose and at 1, 3, 6, 8, 10, 12, 18, 24, and 36 hours postdose, then return on the next 2 days for 48 and 72 hour postdose PK blood samples.
  • Subjects will only receive the morning dose at the Week 12/EOS visit.
  • Safety assessments will be performed at each visit and will include assessment of AEs, vital signs (blood pressure, pulse rate, and oral temperature) , clinical laboratories, physical examination, skin irritation, and electrocardiograms (ECGs) as indicated in the study flow chart, Table 14.
  • a subject must be a male or female between 35 and 85 years of age, inclusive.
  • a subject must have a body mass index between 18.5 and 39.9 kg/m2, inclusive.
  • a subject must have a diagnosis of idiopathic OA according to the American College of Rheumatology clinical and radiographic criteria (knee pain, osteophytes, and at least one of the following: >50 years of age, morning stiffness lasting ⁇ 30 minutes after getting up in the morning, or crepitus) .
  • a subject must have a Kellgren Lawrence Grade of 1 or 2 as determined by the Investigator or a local radiologist at Screening.
  • a subject must have a history of clinically symptomatic mild to moderate OA of the knee for ⁇ 6 months.
  • a subject must have had knee pain while standing, walking, and/or on motion for at least 14 days during the month prior to Screening.
  • a subject must have a knee pain score ⁇ 40 mm and ⁇ 90 mm on a 100 mm VAS (with or without analgesic medication) on at least 10 of the 14 days prior to randomization.
  • a subject must be willing to discontinue any NSAIDs or other analgesic (e.g., aspirin, acetaminophen) or potentially confounding concomitant treatments (e.g., physiotherapy, acupuncture) starting 4 days (or 5 half lives, whichever is longer) before the administration of the first dose of study medication until completing participation in the study.
  • analgesic e.g., aspirin, acetaminophen
  • confounding concomitant treatments e.g., physiotherapy, acupuncture
  • the subject will be allowed to take rescue medication (acetaminophen) for pain during the study except during the 24 hours prior to Baseline (Day1) , Week 2, Week 4, Week 8, Week 12/EOS, and Follow-up assessments.
  • a subject must be willing to discontinue applying any topical preparations containing Vitamin A acids (including all trans retinoic acid (tretinoin) , 13 cis retinoic acid [isotretinoin] , 9 cis retinoic acid [alitretinoin] , vitamin A [retinol] , retinal, and their derivatives) to the lower limbs starting on Day 1 until completing participation in the study.
  • Topical preparations containing Vitamin A acids or retinol may be applied to areas of the skin above the waist, but should not be applied to areas of the skin exposed to study medication.
  • a subject must be willing to avoid unaccustomed physical activity (e.g., starting a new weight lifting routine) for the duration of the study.
  • a subject who has a history of chronic inflammatory disease such as rheumatoid arthritis, psoriatic arthritis, gouty arthritis
  • chronic inflammatory disease such as rheumatoid arthritis, psoriatic arthritis, gouty arthritis
  • fibromyalgia conditions that may affect the target joint (e.g., osteonecrosis, chondrocalcinosis) , or asthma.
  • the test product is a 7%solution of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate hydrochloride in 25%ethanol, which will be administered topically as a spray.
  • the 7%topical spray solution consists of 700 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate hydrochloride (equivalent to 625 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate free base) in 10 mL 25%ethanol (v/v) .
  • the spray bottle deposits 70 mg of spray solution and 4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate free base per spray on the skin.
  • Subjects are to apply each spray to a different skin area around the knee (e.g., lateral, medial, front, and back surfaces of the knee) based on the randomized dose level assigned.
  • the reference therapy is placebo, which will be administered topically as a spray.
  • the spray bottle deposits 70 mg of spray solution per spray on the skin.
  • Subjects are to apply each spray to a different skin area around the knee (e.g., lateral, medial, front, and back surfaces of the knee) based on the randomized dose level assigned.
  • Subjects will not take a shower or wash their knees until at least 8 hours after administration of study medication.
  • Subjects will receive the following treatments BID for 12weeks. On the last day of dose administration (at the Week 12/EOS) visit, subjects will receive 1 dose of study medication in the morning only. The following treatments will be randomly assigned:
  • SAS Safety Analysis Set
  • FAS Full Analysis Set
  • PKAS Pharmacokinetics Analysis Set
  • the PKAS is defined as all subjects who were administered 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and have at least 1 evaluable postdose 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or ibuprofen plasma concentration.
  • the Primary Efficacy Endpoint is the change from Baseline in the WOMAC (VAS) pain subscale score for the target knee at 12 weeks of treatment.
  • VAS WOMAC
  • Subject s global assessment of disease status of the target knee at 2, 4, 8, and 12 weeks of treatment;
  • Subject s global assessment of response to therapy of the target knee at 2, 4, 8, and 12 weeks of treatment;
  • Safety assessments will include AEs, vital signs (blood pressures, pulse rate, and oral temperature) , clinical laboratories, physical examination, skin irritation, and ECGs at various time points during the study as indicated in the study flow chart.
  • Adverse events of interest include: local skin reactions around the treated knee (s) , upper stomach pain, GI bleeding, serious cardiovascular side effects (e.g., thrombotic events, myocardial infarction, or stroke) , jaundice, elevated liver function tests, and nausea.
  • the Primary Efficacy Endpoint is change from Baseline in the WOMAC (VAS) pain subscale score for the target knee at 4 weeks of treatment, and will be analyzed using an analysis of covariance (ANCOVA) . Treatment will be included as a fixed class effect and WOMAC Baseline pain subscale score as covariates.
  • VAS WOMAC
  • ANCOVA analysis of covariance
  • the primary comparisons of interest will be the difference between active Group A (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate/knee) and combined placebo, active Group B (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate/knee) and combined placebo, and active Group C (35 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate/knee) and combined placebo.
  • a sensitivity analysis will also be conducted on the Primary Efficacy Endpoint using an ANCOVA with treatment as a fixed class effect and WOMAC Baseline pain subscale score as covariates, but the comparisons of interest will be the difference between the active and placebo subjects within each treatment group.
  • the Secondary Efficacy Endpoints change from Baseline in the WOMAC subscale scores for pain, stiffness, and functional ability, and overall WOMAC score at 2, 4, 8, and 12 weeks of treatment, will be analyzed using the same methods as for the Primary Efficacy Endpoint.
  • the blinded individual clinical data show the efficacy of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate spray are excellent. Especially, in the middle and high dose cohorts, many patients are almost pain-free at Week 12 (see italicized and bold numbers) .
  • the WOMAC Pain Subscale Scores, WOMAC Joint Stiffness Subscale Scores, and WOMAC Difficulty Performing Daily Activities Subscale Scores are showing in Table 15 through Table 23.
  • PK Data Some patients assigned to receive the placebo had comparable high plasma ibuprofen concentrations as those of patients treated with active drug; and vice versa some patients on active drug had no plasma ibuprofen concentrations more than the blank background (see Tables 24 and 25) .
  • Placebo Effects For OA trials, typically placebo effects reach the maximum at week 2-4 then the placebo effects diminish after 4 weeks. However in this trial, placebo effects increased from week 2 to week 12.
  • Subjects were allowed to take rescue medication (up to six 325 mg tablets [total of 1950 mg] of acetaminophen per day; provided by the Sponsor) for residual knee or other body pain starting at least 4 days (or 5 half lives, whichever is longer) prior to administration of the first dose of study medication except during the 24 hours prior to Baseline (Day 1) , Week 2, Week 4, Week 8, Week 12/end of study (EOS) , and Follow-up assessments. There was a maxium 84.9%decrease in the use of rescue medication, paracetamol, the results of which are shown in Table 40-42.
  • the use of rescue medication for all pain and other conditions was low (less than 100 mg/day/patient for 17.5 mg/knee group and 35 mg/knee group at week 12) during the treatment, especially for a locally used drug.
  • the maximum decrease from pre-treatment to week 12 was up to 75%and the decrease was much larger than the published data.
  • Table 43 The use of rescue medication (paracetamol, mg/day/patient) for other conditions excluding knee pain
  • rescue medication for other conditions excluding knee pain was increased during the treatment than pre-treatment period. This may indicate the less use of rescue medication during the treatment was not from placebo effect.
  • the use of rescue medication for other condition excluding knee pain was less during pre-treatment because other conditions were improved by more often use of rescue medication for knee pain during pre-treatment.
  • ibuprofen and 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate mean maximum plasma concentration and AUC increased as 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate doses increased from 8.75 mg to 35 mg but dose proportionality was not formally demonstrated as topical doses of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate increased from 8.75 mg to 35 mg. Based on observed Cmin and accumulation index of ibuprofen, it can be concluded that steady-state was reached following 5 days of b.i.d. dosing.
  • NSAID nonsteroidal anti inflammatory drugs
  • Subjects taking nonsteroidal anti inflammatory drugs (NSAID) or other analgesics may enroll in the trial, but will discontinue any analgesic therapy for the duration of the study, starting at least 4 days (or 5 half lives, whichever is longer) prior to administration of the first dose of study medication (i.e., for an analgesic washout period before Day 1) .
  • NSAID nonsteroidal anti inflammatory drugs
  • Subjects will be allowed to take rescue medication (up to six 500 mg tablets [total of 3000 mg] of acetaminophen per day; provided by the Sponsor) for residual knee or other body pain starting 4 days (or 5 half lives, whichever is longer) prior to administration of the first dose of study medication except during the 24 hours prior to Baseline (Day 1) , Week 2, Week 4, Week 8, Week 12/end of study (EOS) , and Follow up assessments.
  • a subject After a Screening Period of up to 3 weeks, a subject will be randomly assigned to 1 of 3 treatment groups in a 1: 1: 1 ratio with a 3: 1: 1 ratio of the Testing drug: placebo: oral ibuprofen within each treatment group (i.e., 3 subjects to the testing drug treatment, 1 subject to placebo, and 1 subject to oral ibuprofen) :
  • Each subject will receive study treatment for 12 weeks starting on Day 1. Qualified site personnel will contact subjects 1 week after the first administration of study medication to check if there are any issues with the spray bottles, administration of study medication, or adverse events (AEs) . Subjects will return to the site at 2, 4, 8, and 12 weeks of treatment for efficacy and safety assessments as indicated in the study flow chart.
  • the Week 12 visit will be the EOS visit.
  • subjects On the final day of dose administration (Week 12/EOS visit) , subjects will receive 1 dose of study medication in the morning only; Subjects will have a Follow up visit approximately 14 days after the Week 12/EOS visit.
  • Subjects will record the following information in a Daily Diary starting at Screening: the amount of knee pain in the target knee while walking during the preceding 24 hours (using a 100 mm visual analog scale [VAS] ) , the times and number of sprays for each administration of study medication, the times when the subject washes his/her knees and/or takes a shower, the number of tablets of rescue medication taken that day and the times taken, the reason for taking the rescue medication (e.g., knee pain, headache, low back pain) , any other concomitant medications taken that day, and any AEs occurring that day.
  • VAS visual analog scale
  • the VAS version of the WOMAC will be used for the Primary and Secondary Efficacy Endpoints. Efficacy endpoints will be assessed at Screening and Baseline (Day 1) and at the Week 2, Week 4, Week 8, and Week 12/EOS visits.
  • Safety assessments will be performed at each visit and will include assessment of AEs, vital signs (blood pressure, pulse rate, and oral temperature) , clinical laboratories, physical examination, skin irritation, and electrocardiograms (ECGs) as indicated in the study flow chart, Table 47.
  • a subject must be a male or female between 40 and 75 years of age, inclusive.
  • a subject must have a diagnosis of idiopathic OA according to the American College of Rheumatology clinical and radiographic criteria (knee pain, osteophytes, and at least one of the following: >50 years of age, morning stiffness lasting ⁇ 30 minutes after getting up in the morning, or crepitus) .
  • a subject must have a history of clinically symptomatic mild to moderate OA of the knee for ⁇ 6 months.
  • a subject must have had knee pain while standing, walking, and/or on motion for at least 14 days during the month prior to Screening.
  • a subject must have a knee pain score ⁇ 40 mm and ⁇ 90 mm on a 100 mm VAS (with or without analgesic medication) on at least 10 of the 14 days prior to randomization.
  • a subject must be willing to discontinue any NSAIDs or other analgesic (e.g., aspirin, acetaminophen) or potentially confounding concomitant treatments (e.g., physiotherapy, acupuncture) starting 4 days (or 5 half lives, whichever is longer) before the administration of the first dose of study medication until completing participation in the study.
  • analgesic e.g., aspirin, acetaminophen
  • confounding concomitant treatments e.g., physiotherapy, acupuncture
  • the subject will be allowed to take rescue medication (acetaminophen) for pain during the study except during the 24 hours prior to Baseline (Day1) , Week 2, Week 4, Week 8, Week 12/EOS, and Follow-up assessments.
  • a subject must be willing to discontinue applying any topical preparations containing Vitamin A acids (including all trans retinoic acid (tretinoin) , 13 cis retinoic acid [isotretinoin] , 9 cis retinoic acid [alitretinoin] , vitamin A [retinol] , retinal, and their derivatives) to the lower limbs starting on Day 1 until completing participation in the study.
  • Topical preparations containing Vitamin A acids or retinol may be applied to areas of the skin above the waist, but should not be applied to areas of the skin exposed to study medication.
  • a subject must be willing to avoid unaccustomed physical activity (e.g., starting a new weight lifting routine) for the duration of the study.
  • a subject who has a history of chronic inflammatory disease such as rheumatoid arthritis, psoriatic arthritis, gouty arthritis
  • chronic inflammatory disease such as rheumatoid arthritis, psoriatic arthritis, gouty arthritis
  • fibromyalgia conditions that may affect the target joint (e.g., osteonecrosis, chondrocalcinosis) , or asthma.
  • the test product is a 7%solution of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate hydrochloride in 25%ethanol, which will be administered topically as a spray.
  • the 7%topical spray solution consists of 700 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate hydrochloride (equivalent to 625 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate free base) in 10 mL 25%ethanol (v/v) .
  • the spray bottle deposits 70 mg of spray solution and 4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate (free base) per spray on the skin.
  • Subjects are to apply each spray to a different skin area around the knee (e.g., lateral, medial, front, and back surfaces of the knee) based on the randomized dose level assigned.
  • the reference therapy is placebo, which will be administered topically as a spray.
  • the spray bottle deposits 70 mg of spray solution per spray on the skin.
  • Subjects are to apply each spray to a different skin area around the knee (e.g., lateral, medial, front, and back surfaces of the knee) based on the randomized dose level assigned.
  • Subjects will not take a shower or wash their knees until at least 8 hours after administration of study medication.
  • Subjects will receive the following treatments BID for 12weeks. On the last day of dose administration (at the Week 12/EOS) visit, subjects will receive 1 dose of study medication in the morning only. The following treatments will be randomly assigned:
  • Treatment Period 12 weeks.
  • SAS Safety Analysis Set
  • FAS Full Analysis Set
  • PKAS Pharmacokinetics Analysis Set
  • the PKAS is defined as all subjects who were administered 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and have at least 1 evaluable postdose 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate and/or ibuprofen plasma concentration.
  • the Primary Efficacy Endpoint is the change from Baseline in the WOMAC (VAS) pain subscale score for the target knee at 12 weeks of treatment.
  • Subject s global assessment of disease status of the target knee at 2, 4, 8, and 12 weeks of treatment;
  • Subject s global assessment of response to therapy of the target knee at 2, 4, 8, and 12 weeks of treatment;
  • VAS WOMAC
  • Safety assessments will include AEs, vital signs (blood pressures, pulse rate, and oral temperature) , clinical laboratories, physical examination, skin irritation, and ECGs at various time points during the study as indicated in the study flow chart.
  • Adverse events of interest include: local skin reactions around the treated knee (s) , upper stomach pain, GI bleeding, serious cardiovascular side effects (e.g., thrombotic events, myocardial infarction, or stroke) , jaundice, elevated liver function tests, and nausea.
  • the Primary Efficacy Endpoint is change from Baseline in the WOMAC (VAS) pain subscale score for the target knee at 4 weeks of treatment, and will be analyzed using an analysis of covariance (ANCOVA) . Treatment will be included as a fixed class effect and WOMAC Baseline pain subscale score as covariates.
  • VAS WOMAC
  • ANCOVA analysis of covariance
  • the primary comparisons of interest will be the difference between active Group A (4.375 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate/knee) and combined placebo, active Group B (8.75 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate/knee) and combined placebo, and active Group C (17.5 mg 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate/knee) and combined placebo.
  • a sensitivity analysis will also be conducted on the Primary Efficacy Endpoint using an ANCOVA with treatment as a fixed class effect and WOMAC Baseline pain subscale score as covariates, but the comparisons of interest will be the difference between the active and placebo subjects within each treatment group.
  • the Secondary Efficacy Endpoints change from Baseline in the WOMAC subscale scores for pain, stiffness, and functional ability, and overall WOMAC score at 2, 4, 8, and 12 weeks of treatment, will be analyzed using the same methods as for the Primary Efficacy Endpoint.
  • Tables 48-61 show the clinical data of the first 130 subjects (from Randomization number 001-130) .
  • WOMAC As shown by the reduction in pain, stiffness, functional ability severity in the patient’s assessment in WOMAC (VAS) subscale scores, WOMAC overall scores, the Subject’s Global Assessment of Disease Status scores (SGADS) , and the Subject’s pain Assessment Scores (SPA) , 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate can reduce the signs and symptoms of osteoarthritis in a dose response manner.
  • VAS WOMAC subscale scores
  • SGADS Global Assessment of Disease Status scores
  • SPA pain Assessment Scores
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate can reduce the signs and symptoms of osteoarthritis in a dose response manner.
  • the 17.5 mg/knee of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate, BID has much higher efficacy than oral ibuprofen (3 ⁇ 400 mg/day, -14.5 mm in pain, -12.4 mm in stiffness, -15.6 in functional ability, -15.2 mm in WOMAC overall, -14.2 mm in SGADS, and -14.1 mm in SPA) and placebo (-15.0 mm in pain, -19.1 mm in stiffness, -19.1 in functional ability, -18.2 mm in WOMAC overall, -18.6 mm in SGADS, and -21.0 mm in SPA) significantly.
  • the efficacy (measured by overall of the six scores) of ibuprofen is better than placebo, but not significantly.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is a prodrug of ibuprofen which can penetrate cartilage, skin, and bone in a very high rate and >99.9%of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is metabolized to ibuprofen in any human tissue (except skin, the in vitro T1/2 of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate with animal skin is ⁇ 20 hours) in a very short time (2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is very difficult to be detected in plasma due to the very short T1/2 (in vitro: ⁇ 4 min.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is designed to minimize the plasma exposure to minimize side effects and maximize the local tissue exposure to maximize the efficacy.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate (9 mg/kg, equal to 6.73 mg/kg ibuprofen sodium) administered to mini pig transdermally the plasma exposure (AUC last 1516 h ng/mL) is only ⁇ 10%of the plasma exposure (AUC last 15466 h ng/mL) of oral ibuprofen sodium and the C max (38.61 ng/mL) is less than 0.3%C max (13110.55 ng/mL) of oral ibuprofen, however the cartilage exposure (AUC last 23.91 h ⁇ g/mL) and muscle exposure (AUC last 35.89 h ⁇ g/mL) are 8-9 time higher than that of
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate can reduce the signs and symptoms of osteoarthritis in a dose response manner: the efficacy of 17.5 mg/knee of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate, BID > 8.75 mg/knee of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate >4.375 mg/knee of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate > 3 ⁇ 400 mg of
  • the 17.5 mg/knee of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate, BID is better than oral ibuprofen (3 ⁇ 400 mg/day) and placebo significantly, the differences from oral ibuprofen: -14.5 mm in pain, -12.4 mm in stiffness, -15.6 in functional ability, -15.2 mm in WOMAC overall, -14.2 in SGADS, and -14.1 in SPA; and from placebo: -15.0 mm in pain, -19.1 mm in stiffness, -19.1 in functional ability, -18.2 mm in WOMAC overall, -18.6 mm in SGADS, and -21.0 mm in SPA.
  • oral ibuprofen 3 ⁇ 400 mg
  • placebo is quite small: -0.5 mm in pain, -6.7 mm in stiffness, -3.5 mm in functional ability, -3.0 mm in WOMAC overall, -4.2 mm in the Subject’s Global Assessment of Disease Status scores, and 6.1 mm in the Subject’s pain Assessment Scores, however, in the “good and very good” rate of the Subject Global Impression of Change is 55% (oral ibuprofen) vs. 20% (placebo) (17.5 mg/knee, BID of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate is 73.7%) and the difference is very clear.
  • the first reason may be the sample size is small, the second one may be the placebo effects are higher in Asian subjects.
  • Margaret N Essex etc. (4 researchers are all Pfizer employees) reported a small different from placebo in subjects with Asian descent in 31 centers in the US in compliance with the principles of Good Clinical Practice and the Declaration of Helsinki: celecoxib vs. placebo: -5.6 mm (0-20 mm) vs. -4.3 mm (0-20 mm) , difference: -1.3 mm (0-20 mm) or -6.5 mm (0-100 mm) in WOMAC pain; -17.3 mm (0-68 mm) vs.
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate can be the first high effective and safe OA drug for everyday use, and the subjects in high dose group have average scores below 30 mm at Week 12 in all six subscales, that may mean that people with OA will have a normal life with every day use of 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate.
  • Table 58 Change from Baseline in the WOMAC*Difficulty Performing Daily Activities Subscale Scores from Week 2 to Week 12
  • Table 60 The Change from Baseline in the Subject’s Global Assessment of Disease Status Scores from Week 2 to Week 12
  • Table 68 Efficacy Analysis of Change from Baseline in the Subject’s pain Assessment Scores at Week 12
  • Table 69 Efficacy Analysis in Subject Global Impression of Change (SGIC) , Investigator’s global assessment of disease status (IGADS) , and in Investigator’s assessment of response to therapy (IART) at Week 12
  • WOMAC As shown by the reduction in pain, stiffness, functional ability severity in the patient’s assessment in WOMAC (VAS) pain subscale scores, WOMAC overall scores, the Subject’s Global Assessment of Disease Status scores (SGADS) , and the Subject’s pain Assessment Scores (SPA) , 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate can reduce the signs and symptoms of osteoarthritis in a dose response manner.
  • VAS WOMAC
  • SGADS Global Assessment of Disease Status scores
  • SPA pain Assessment Scores
  • 2- (diethylamino) ethyl 2- (4-isobutylphenyl) propionate can reduce the signs and symptoms of osteoarthritis in a dose response manner.

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Abstract

La présente invention concerne le propionate de 2-(diéthylamino)éthyl-2-(4-isobutylphényle) ou des sels de qualité pharmaceutique de celui-ci. En outre, sont divulgués, pour une utilisation et des méthodes pour le traitement de diverses douleurs et de l'inflammation, en particulier de l'arthrose, des compositions pharmaceutiques, des kits et des dispositifs de traitement comprenant du propionate de 2-(diéthylamino)éthyl-2-(4-isobutylphényle) et/ou des sels de qualité pharmaceutique de celui-ci, ainsi que des formes posologiques, des dosages et des méthodes d'utilisation de ceux-ci par administration topique, pour le traitement de diverses douleurs et de l'inflammation, en particulier de l'arthrose.
EP21818935.5A 2020-06-05 2021-06-04 Administration topique de propionate de 2-(diéthylamino)éthyl-2-(4-isobutylphényle) pour le traitement de maladies Pending EP4222139A1 (fr)

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